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Nivolumab shows promise for pretreated advanced HCC
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
SAN FRANCISCO – Nivolumab was associated with durable responses in heavily pretreated patients with advanced hepatocellular carcinoma in the dose-escalation and dose-expansion phases of the CheckMate 040 study.
Further, the safety profile of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), was consistent with that observed in other solid tumors; events were manageable, and no new safety signals were detected, Ignacio Melero, MD, of Clinica Universidad de Navarra, Pamplona, Spain, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
In all, 262 patients with histologically confirmed advanced disease not amenable to curative resection were treated across the CheckMate 040 dose-escalation phase (phase I), which evaluated 0.1-10 mg/kg of nivolumab given every 2 weeks, and the dose-expansion phase (phase II), which involved nivolumab at a dose of 3 mg/kg every 2 weeks in four cohorts: sorafenib naive/intolerant patients, sorafenib progressors, hepatitis C virus-infected patients, and hepatitis B virus-infected patients.
“Because of the inflammation that often afflicts the liver, we were very afraid of precipitating hyper-acute or fulminant hepatitis in these patients, and that was the reason we undertook a very careful dose escalation,” Dr. Melero said, adding that due to efficacy and safety results in the dose escalation phase, the 3-mg/kg dose used in other clinical trials was expanded to all subjects, including uninfected patients and those with HCV or HBV infection.
In regard to safety and tolerability – the primary endpoint of phase I – grade 3/4 treatment-related adverse events occurred in 20% of patients. No maximum tolerated dose was reached during dose escalation, Dr. Melero said.
The most common reason for treatment discontinuation was disease progression; very few patients discontinued for toxicity, he said, noting that “the safety profile was very consistent with what has been reported in other indications.”
In fact, most grade 3/4 events involved laboratory abnormalities without clinical repercussions, he said.
The safety profile in phase II was consistent with that observed in phase I, and no differences in safety were seen in the three categories of hepatocellular carcinoma patients in the study.
In regard to objective response – the primary endpoint of phase II – the investigator-assessed rates were 16.2% in phase I and 18.6% in phase II, and the rates assessed by blinded independent central review were 18.9% and 14.5% in the phases, respectively. Based on imaging assessed using modified RESIST criteria, the rates were 21.6% and 18.6%, respectively.
The median duration of response was 17.1 months in phase I, and had not yet been reached in phase II, Dr. Melero said, adding that in uninfected patients, an “important number of patients developed stable disease that was durable.”
This also was seen in patients with chronic hepatitis, he noted.
“We believe that stabilization of disease is a driver of survival, because we have seen that in dose escalation, 45% of patients were alive 18 months after treatment onset, and at last data base log [in dose escalation], 71% were alive 9 months after starting treatment,” he said.
Of note, objective response rates were similar in patients treated with sorafenib and in those who received nivolumab as first-line treatment, and they were similar regardless of tumor programmed death-ligand 1 (PD-L1) expression.
Quality of life, as reported by patients via EQ-5D questionnaire, remained stable over time.
Study subjects had a median age of 63 years, and were heavily pretreated – most often by sorafenib.
Hepatocellular carcinoma diagnosed at advanced stages has a poor prognosis, and those who progress on sorafenib – the only systemic therapy option in such patients – have few options, Dr. Melero said.
Nivolumab, which has been shown to restore T-cell–mediated antitumor activity, has demonstrated clinical and survival benefit in a number of tumor types.
The current findings suggest that it also is a promising alternative for advanced hepatocellular carcinoma.
“Nivolumab demonstrated objective responses and long-term survival in both sorafenib-experienced and sorafenib-naive patients. Nivolumab monotherapy provided early, stable and durable responses when they took place, efficacy was observed irrespective of chronic viral infection by hepatitis viruses, and responses were also observed in PD-L1-negative cases upon examination of biopsies,” he concluded, noting that a randomized phase III trial comparing nivolumab with systemic sorafenib is ongoing.
CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Investigator-assessed objective response rates were 16.2% in phase I and 18.6% in phase II.
Data source: The CheckMate 040 phase I and phase II clinical studies involving 262 patients.
Disclosures: CheckMate 040 was sponsored by Bristol Myers Squibb. Dr. Melero reported receiving honoraria from and serving as a consultant or adviser for AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche, and reported research funding to his institution from Alligator Bioscience, Pfizer, and Tusk Therapeutics.
AGA Guideline: Acute liver failure
Physicians should avoid routinely testing patients with acute liver failure for Wilson’s disease unless there is “high clinical suspicion” for the disorder, according to a new guideline from the AGA Institute.
Wilson’s disease so rarely accompanies acute liver failure that a positive test will have low predictive value, Steven L. Flamm, MD, of Northwestern University, Chicago, and his associates wrote in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.12.026). Diagnosing Wilson’s disease also is unlikely to change treatment “because liver transplantation is the ultimate outcome,” they emphasize.
The guideline grades seven recommendations as “conditional” based on “very-low” quality evidence. These include the statement on Wilson’s disease testing, plus suggestions to test and treat patients with ALF for herpes simplex virus (HSV) infection, to test pregnant patients for hepatitis E virus infection, and to perform autoantibody testing for autoimmune hepatitis. Case series report only about a 1% prevalence of HSV infection in ALF, and there is little information on diagnostic accuracy or treatment in this setting, the guidelines state. Although acyclovir is relatively safe and inexpensive, data on efficacy is limited to “a suggestion on a case-report level that patients with acute hepatitis secondary to HSV do better with treatment than without.”
The guideline also conditionally recommends against routine testing for varicella zoster virus infection and routine liver biopsy in ALF. The authors note only about 10 case reports of varicella zoster–associated ALF and few data on how liver biopsy results in ALF alter treatment plan, outcome, or the choice to seek liver transplantation. The experts do recommend prognostic scoring with Model for End-Stage Liver Disease, which pooled analyses have found to be more sensitive than King’s College Criteria, they wrote.
The guideline conditionally recommends against empirically treating elevated intracranial pressure in ALF, on the basis of five randomized trials that found no overall mortality benefit of moderate hypothermia, hypertonic saline, L-ornithine, L-aspartate, intravenous mannitol, or hyperventilation.
The experts cite insufficient evidence to recommend using N-acetyl cysteine in patients whose ALF is not associated with acetaminophen exposure. Likewise, they find inadequate data to make any recommendation about using extracorporeal liver support systems outside of the setting of clinical trials. Although such systems can “potentially” buy time for patients to either spontaneously recover without transplant or survive longer on the transplantation list, three systematic reviews found “no clear effect on mortality,” and randomized trials reported either null results or a “marginally significant survival benefit” in the face of steep costs and potentially significant toxicities, the authors emphasize.
None of the experts had relevant financial disclosures.
Physicians should avoid routinely testing patients with acute liver failure for Wilson’s disease unless there is “high clinical suspicion” for the disorder, according to a new guideline from the AGA Institute.
Wilson’s disease so rarely accompanies acute liver failure that a positive test will have low predictive value, Steven L. Flamm, MD, of Northwestern University, Chicago, and his associates wrote in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.12.026). Diagnosing Wilson’s disease also is unlikely to change treatment “because liver transplantation is the ultimate outcome,” they emphasize.
The guideline grades seven recommendations as “conditional” based on “very-low” quality evidence. These include the statement on Wilson’s disease testing, plus suggestions to test and treat patients with ALF for herpes simplex virus (HSV) infection, to test pregnant patients for hepatitis E virus infection, and to perform autoantibody testing for autoimmune hepatitis. Case series report only about a 1% prevalence of HSV infection in ALF, and there is little information on diagnostic accuracy or treatment in this setting, the guidelines state. Although acyclovir is relatively safe and inexpensive, data on efficacy is limited to “a suggestion on a case-report level that patients with acute hepatitis secondary to HSV do better with treatment than without.”
The guideline also conditionally recommends against routine testing for varicella zoster virus infection and routine liver biopsy in ALF. The authors note only about 10 case reports of varicella zoster–associated ALF and few data on how liver biopsy results in ALF alter treatment plan, outcome, or the choice to seek liver transplantation. The experts do recommend prognostic scoring with Model for End-Stage Liver Disease, which pooled analyses have found to be more sensitive than King’s College Criteria, they wrote.
The guideline conditionally recommends against empirically treating elevated intracranial pressure in ALF, on the basis of five randomized trials that found no overall mortality benefit of moderate hypothermia, hypertonic saline, L-ornithine, L-aspartate, intravenous mannitol, or hyperventilation.
The experts cite insufficient evidence to recommend using N-acetyl cysteine in patients whose ALF is not associated with acetaminophen exposure. Likewise, they find inadequate data to make any recommendation about using extracorporeal liver support systems outside of the setting of clinical trials. Although such systems can “potentially” buy time for patients to either spontaneously recover without transplant or survive longer on the transplantation list, three systematic reviews found “no clear effect on mortality,” and randomized trials reported either null results or a “marginally significant survival benefit” in the face of steep costs and potentially significant toxicities, the authors emphasize.
None of the experts had relevant financial disclosures.
Physicians should avoid routinely testing patients with acute liver failure for Wilson’s disease unless there is “high clinical suspicion” for the disorder, according to a new guideline from the AGA Institute.
Wilson’s disease so rarely accompanies acute liver failure that a positive test will have low predictive value, Steven L. Flamm, MD, of Northwestern University, Chicago, and his associates wrote in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.12.026). Diagnosing Wilson’s disease also is unlikely to change treatment “because liver transplantation is the ultimate outcome,” they emphasize.
The guideline grades seven recommendations as “conditional” based on “very-low” quality evidence. These include the statement on Wilson’s disease testing, plus suggestions to test and treat patients with ALF for herpes simplex virus (HSV) infection, to test pregnant patients for hepatitis E virus infection, and to perform autoantibody testing for autoimmune hepatitis. Case series report only about a 1% prevalence of HSV infection in ALF, and there is little information on diagnostic accuracy or treatment in this setting, the guidelines state. Although acyclovir is relatively safe and inexpensive, data on efficacy is limited to “a suggestion on a case-report level that patients with acute hepatitis secondary to HSV do better with treatment than without.”
The guideline also conditionally recommends against routine testing for varicella zoster virus infection and routine liver biopsy in ALF. The authors note only about 10 case reports of varicella zoster–associated ALF and few data on how liver biopsy results in ALF alter treatment plan, outcome, or the choice to seek liver transplantation. The experts do recommend prognostic scoring with Model for End-Stage Liver Disease, which pooled analyses have found to be more sensitive than King’s College Criteria, they wrote.
The guideline conditionally recommends against empirically treating elevated intracranial pressure in ALF, on the basis of five randomized trials that found no overall mortality benefit of moderate hypothermia, hypertonic saline, L-ornithine, L-aspartate, intravenous mannitol, or hyperventilation.
The experts cite insufficient evidence to recommend using N-acetyl cysteine in patients whose ALF is not associated with acetaminophen exposure. Likewise, they find inadequate data to make any recommendation about using extracorporeal liver support systems outside of the setting of clinical trials. Although such systems can “potentially” buy time for patients to either spontaneously recover without transplant or survive longer on the transplantation list, three systematic reviews found “no clear effect on mortality,” and randomized trials reported either null results or a “marginally significant survival benefit” in the face of steep costs and potentially significant toxicities, the authors emphasize.
None of the experts had relevant financial disclosures.
FROM GASTROENTEROLOGY
VIDEO: Sofosbuvir with velpatasvir beat other HCV GT3 regimens
Regimens containing sofosbuvir and velpatasvir were most effective for treating both cirrhotic and noncirrhotic genotype 3 hepatitis C virus infection (HCV GT3), according to a meta-analysis reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.03).
“Our analyses indicated that ribavirin significantly increases SVR [sustained viral response] rates and should be considered, if tolerated,” added Floor A.C. Berden, MD, of Radboud University Medical Center, Nijmegen, the Netherlands, and her associates.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Direct-acting antiviral regimens successfully treat chronic HCV infection, but tend to perform suboptimally in HCV GT3, especially when patients are treatment experienced and have cirrhosis. Options for HCV GT3 infection include sofosbuvir combined with ribavirin, daclatasvir, or velpatasvir. But head-to-head trials of these regimens are lacking, and are unlikely to occur, in part because the Food and Drug Administration permits single-arm trials with historical controls as the comparator, the investigators said.
Therefore, they searched PubMed, Embase, and the Web of Science database through March 15, 2016, for randomized trials and real-world studies of at least one direct-acting antiviral agent in adults with chronic HCV GT3 infection. They also manually searched abstracts presented at the 2015 conferences of the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. This work yielded 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies. The researchers used a Bayesian analysis based on Markov chain Monte Carlo methods.
For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin yielded the highest estimated likelihood of SVR (99%; 95% confidence interval, 98%-100%), followed by sofosbuvir and velpatasvir without ribavirin (97%; 95% CI, 95%-99%), sofosbuvir and daclatasvir with ribavirin (96%; 95% CI, 92%-98%), and sofosbuvir and peginterferon with ribavirin (95%; 95% CI, 91%-98%), all for 12 weeks, the investigators reported.
For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%; 95% CI, 92%-99%), followed by sofosbuvir and daclatasvir with ribavirin for 24 weeks (94%; 95% CI, 87%-98%), sofosbuvir and velpatasvir and ribavirin for 12 weeks (94%; 95% CI, 86%-98%). The estimated efficacy of sofosbuvir and velpatasvir held up in sensitivity analyses that honed in on studies with a low risk of bias, approved regimens, or those under regulatory evaluation, patients without decompensated cirrhosis, and patients without HIV coinfection.
Adding ribavirin to a direct-acting antiviral regimen improved the odds of SVR about 2.6-fold (95% CI, 1.3-4.7) among noncirrhotic patients and by about 4.5 times in cirrhotic patients (95% CI, 2.5-7.7), the investigators reported. “In clinical practice, choice of treatment may depend on several factors, such as availability and price of direct-acting antivirals, tolerance of ribavirin, risk of adverse events or drug-drug interactions, and the presence of resistance-associated substitutions,” they added. Nonetheless, these findings can help prioritize therapies for HCV GT3 infection in both clinical guidelines and practice, they emphasized.
Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.
The rapid development of direct-acting antiviral agents (DAAs) to treat hepatitis C has yielded many surprises and left some gaps in our knowledge.
One of the surprises was that genotype 3, previously considered “easier to treat,” proved quite resistant to the first generation of DAAs. One of the gaps in knowledge was a lack of randomized and head-to-head trials for current medications. One could argue that randomized trials have limited utility in a disease with essentially no spontaneous cures, and that head-to-head trials are pointless in a rapidly evolving field where regimens may be obsolete by the time the study is completed.
On the bright side, a hard endpoint like sustained virologic response (SVR) makes comparison between trials possible. The paper by Bergen et al. offers some guidance in closing the knowledge gap. Their meta-analysis using Bayesian Markov Chain Monte Carlo methods examined the effectiveness of currently available antiviral agents in 27 studies that focused entirely on genotype 3. All studies used antiviral agents that are currently available in the United States, and effectiveness was tested in both noncirrhotic and cirrhotic patients.
The evolution of antiviral therapy has been amazing. After decades of incremental gains, we entered an era of dizzying progress. Genotype 3 went from great news to bad news, and genotype 1 went from a scourge to a piece of cake.
Norman L. Sussman, MD, is associate professor of surgery, Baylor College of Medicine, Houston; director, Project ECHO. He has received speaking and consulting fees for AbbVie, BMS, Gilead, and Merck.
The rapid development of direct-acting antiviral agents (DAAs) to treat hepatitis C has yielded many surprises and left some gaps in our knowledge.
One of the surprises was that genotype 3, previously considered “easier to treat,” proved quite resistant to the first generation of DAAs. One of the gaps in knowledge was a lack of randomized and head-to-head trials for current medications. One could argue that randomized trials have limited utility in a disease with essentially no spontaneous cures, and that head-to-head trials are pointless in a rapidly evolving field where regimens may be obsolete by the time the study is completed.
On the bright side, a hard endpoint like sustained virologic response (SVR) makes comparison between trials possible. The paper by Bergen et al. offers some guidance in closing the knowledge gap. Their meta-analysis using Bayesian Markov Chain Monte Carlo methods examined the effectiveness of currently available antiviral agents in 27 studies that focused entirely on genotype 3. All studies used antiviral agents that are currently available in the United States, and effectiveness was tested in both noncirrhotic and cirrhotic patients.
The evolution of antiviral therapy has been amazing. After decades of incremental gains, we entered an era of dizzying progress. Genotype 3 went from great news to bad news, and genotype 1 went from a scourge to a piece of cake.
Norman L. Sussman, MD, is associate professor of surgery, Baylor College of Medicine, Houston; director, Project ECHO. He has received speaking and consulting fees for AbbVie, BMS, Gilead, and Merck.
The rapid development of direct-acting antiviral agents (DAAs) to treat hepatitis C has yielded many surprises and left some gaps in our knowledge.
One of the surprises was that genotype 3, previously considered “easier to treat,” proved quite resistant to the first generation of DAAs. One of the gaps in knowledge was a lack of randomized and head-to-head trials for current medications. One could argue that randomized trials have limited utility in a disease with essentially no spontaneous cures, and that head-to-head trials are pointless in a rapidly evolving field where regimens may be obsolete by the time the study is completed.
On the bright side, a hard endpoint like sustained virologic response (SVR) makes comparison between trials possible. The paper by Bergen et al. offers some guidance in closing the knowledge gap. Their meta-analysis using Bayesian Markov Chain Monte Carlo methods examined the effectiveness of currently available antiviral agents in 27 studies that focused entirely on genotype 3. All studies used antiviral agents that are currently available in the United States, and effectiveness was tested in both noncirrhotic and cirrhotic patients.
The evolution of antiviral therapy has been amazing. After decades of incremental gains, we entered an era of dizzying progress. Genotype 3 went from great news to bad news, and genotype 1 went from a scourge to a piece of cake.
Norman L. Sussman, MD, is associate professor of surgery, Baylor College of Medicine, Houston; director, Project ECHO. He has received speaking and consulting fees for AbbVie, BMS, Gilead, and Merck.
Regimens containing sofosbuvir and velpatasvir were most effective for treating both cirrhotic and noncirrhotic genotype 3 hepatitis C virus infection (HCV GT3), according to a meta-analysis reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.03).
“Our analyses indicated that ribavirin significantly increases SVR [sustained viral response] rates and should be considered, if tolerated,” added Floor A.C. Berden, MD, of Radboud University Medical Center, Nijmegen, the Netherlands, and her associates.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Direct-acting antiviral regimens successfully treat chronic HCV infection, but tend to perform suboptimally in HCV GT3, especially when patients are treatment experienced and have cirrhosis. Options for HCV GT3 infection include sofosbuvir combined with ribavirin, daclatasvir, or velpatasvir. But head-to-head trials of these regimens are lacking, and are unlikely to occur, in part because the Food and Drug Administration permits single-arm trials with historical controls as the comparator, the investigators said.
Therefore, they searched PubMed, Embase, and the Web of Science database through March 15, 2016, for randomized trials and real-world studies of at least one direct-acting antiviral agent in adults with chronic HCV GT3 infection. They also manually searched abstracts presented at the 2015 conferences of the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. This work yielded 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies. The researchers used a Bayesian analysis based on Markov chain Monte Carlo methods.
For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin yielded the highest estimated likelihood of SVR (99%; 95% confidence interval, 98%-100%), followed by sofosbuvir and velpatasvir without ribavirin (97%; 95% CI, 95%-99%), sofosbuvir and daclatasvir with ribavirin (96%; 95% CI, 92%-98%), and sofosbuvir and peginterferon with ribavirin (95%; 95% CI, 91%-98%), all for 12 weeks, the investigators reported.
For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%; 95% CI, 92%-99%), followed by sofosbuvir and daclatasvir with ribavirin for 24 weeks (94%; 95% CI, 87%-98%), sofosbuvir and velpatasvir and ribavirin for 12 weeks (94%; 95% CI, 86%-98%). The estimated efficacy of sofosbuvir and velpatasvir held up in sensitivity analyses that honed in on studies with a low risk of bias, approved regimens, or those under regulatory evaluation, patients without decompensated cirrhosis, and patients without HIV coinfection.
Adding ribavirin to a direct-acting antiviral regimen improved the odds of SVR about 2.6-fold (95% CI, 1.3-4.7) among noncirrhotic patients and by about 4.5 times in cirrhotic patients (95% CI, 2.5-7.7), the investigators reported. “In clinical practice, choice of treatment may depend on several factors, such as availability and price of direct-acting antivirals, tolerance of ribavirin, risk of adverse events or drug-drug interactions, and the presence of resistance-associated substitutions,” they added. Nonetheless, these findings can help prioritize therapies for HCV GT3 infection in both clinical guidelines and practice, they emphasized.
Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.
Regimens containing sofosbuvir and velpatasvir were most effective for treating both cirrhotic and noncirrhotic genotype 3 hepatitis C virus infection (HCV GT3), according to a meta-analysis reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.03).
“Our analyses indicated that ribavirin significantly increases SVR [sustained viral response] rates and should be considered, if tolerated,” added Floor A.C. Berden, MD, of Radboud University Medical Center, Nijmegen, the Netherlands, and her associates.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Direct-acting antiviral regimens successfully treat chronic HCV infection, but tend to perform suboptimally in HCV GT3, especially when patients are treatment experienced and have cirrhosis. Options for HCV GT3 infection include sofosbuvir combined with ribavirin, daclatasvir, or velpatasvir. But head-to-head trials of these regimens are lacking, and are unlikely to occur, in part because the Food and Drug Administration permits single-arm trials with historical controls as the comparator, the investigators said.
Therefore, they searched PubMed, Embase, and the Web of Science database through March 15, 2016, for randomized trials and real-world studies of at least one direct-acting antiviral agent in adults with chronic HCV GT3 infection. They also manually searched abstracts presented at the 2015 conferences of the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. This work yielded 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies. The researchers used a Bayesian analysis based on Markov chain Monte Carlo methods.
For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin yielded the highest estimated likelihood of SVR (99%; 95% confidence interval, 98%-100%), followed by sofosbuvir and velpatasvir without ribavirin (97%; 95% CI, 95%-99%), sofosbuvir and daclatasvir with ribavirin (96%; 95% CI, 92%-98%), and sofosbuvir and peginterferon with ribavirin (95%; 95% CI, 91%-98%), all for 12 weeks, the investigators reported.
For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%; 95% CI, 92%-99%), followed by sofosbuvir and daclatasvir with ribavirin for 24 weeks (94%; 95% CI, 87%-98%), sofosbuvir and velpatasvir and ribavirin for 12 weeks (94%; 95% CI, 86%-98%). The estimated efficacy of sofosbuvir and velpatasvir held up in sensitivity analyses that honed in on studies with a low risk of bias, approved regimens, or those under regulatory evaluation, patients without decompensated cirrhosis, and patients without HIV coinfection.
Adding ribavirin to a direct-acting antiviral regimen improved the odds of SVR about 2.6-fold (95% CI, 1.3-4.7) among noncirrhotic patients and by about 4.5 times in cirrhotic patients (95% CI, 2.5-7.7), the investigators reported. “In clinical practice, choice of treatment may depend on several factors, such as availability and price of direct-acting antivirals, tolerance of ribavirin, risk of adverse events or drug-drug interactions, and the presence of resistance-associated substitutions,” they added. Nonetheless, these findings can help prioritize therapies for HCV GT3 infection in both clinical guidelines and practice, they emphasized.
Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point. Regimens containing sofosbuvir and velpatasvir were more effective than were other direct-acting antiviral combinations for treating genotype 3 hepatitis C virus infection, regardless of cirrhosis status.
Major finding: For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin for 12 weeks yielded the highest estimated likelihood of sustained viral response (99%). For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%).
Data source: A systematic review and meta-analysis of 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies.
Disclosures: Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.
Interval cholecystectomy may be a risky business
HOLLYWOOD, FLA – Interval cholecystectomy remains a challenging procedure, with longer operative times and ICU stays, greater blood loss, more biliary and bowel injuries, and even hints of increased mortality, compared with immediate cholecystectomy, according to the findings from a retrospective study of 404 patients.
The staged procedure, completed after antibiotic therapy and percutaneous cholecystostomy, has been increasing in frequency over the past 10 years, but has not been rigorously studied, James Ackerman, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
“Looking at Medicare data over the past decade, we see a 50% increase in this procedure, which is marked by some striking regional variation,” from 5% of acute cholecystitis cases in the Northeast to less than 1% in some other regions. “This shows that as a group, we really don’t know what to do with this procedure.”
The revised Tokyo Guidelines for the management of acute cholangitis and cholecystitis aren’t hugely helpful either, noted Dr. Ackerman of the University of Pittsburgh Medical Center. While the guidelines are fairly straightforward for patients with grade 1 and grade 3 disease, “there’s a lot of gray area in grade 2.”
Treatment for these patients should include biliary drainage with antibiotics, but, he said, the recommendations for surgery, and whether it should be elective, immediate, or delayed, can be confusing for this group.
Dr. Ackerman’s retrospective analysis comprised 177 patients with acute cholecystitis who underwent an interval cholecystectomy (IC) after percutaneous cholecystostomy, and 227 controls who underwent an immediate cholecystectomy. The analysis spanned 2008-2013 and used data from seven hospitals in one health care system.
Patients who had the IC were older (70 vs. 55 years), had a worse American Society of Anesthesiologists class (3 vs. 2.5), and a worse Tokyo Grade (2 vs. 1).
Most of the IC procedures (119) were laparoscopic. There were 43 conversions to open and 15 were planned open surgeries. Among the immediate cholecystectomies, most (192) were laparoscopic. There were 28 conversions to open and six planned open surgeries.
The conversion rate was significantly higher among the IC group (28% vs.13%). The most common reasons for conversion were hostile abdomen (48% vs. 16%) and hostile right upper quadrant (34% vs. 58%).
Operating time was significantly longer in the IC group (121 vs. 90 minutes). Estimated blood loss was also significantly higher (30 vs. 15 cc). Total hospital stay was significantly longer (7 vs. 5 days), as was ICU stay (1 vs. 0.1 day).
There were no biliary tract injuries in the cholecystectomy group, while 5.7% of IC patients sustained such an injury. Bowel injuries, most often serosal, were also more common in the IC group (6% vs. 0.4%). The IC group had more surgical site infections as well (12% vs. 0.44%).
There was no significant difference in 30-day mortality, but at 1 year, IC patients were significantly more likely to have died (15% vs. 0.44%).
The ongoing CHOCOLATE trial (Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy) may help clarify the issue further, Dr. Ackerman said. The study being conducted in the Netherlands is randomizing high-risk cholecystitis patients to either laparoscopic cholecystectomy or percutaneous drainage.
Dr. Ackerman had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
HOLLYWOOD, FLA – Interval cholecystectomy remains a challenging procedure, with longer operative times and ICU stays, greater blood loss, more biliary and bowel injuries, and even hints of increased mortality, compared with immediate cholecystectomy, according to the findings from a retrospective study of 404 patients.
The staged procedure, completed after antibiotic therapy and percutaneous cholecystostomy, has been increasing in frequency over the past 10 years, but has not been rigorously studied, James Ackerman, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
“Looking at Medicare data over the past decade, we see a 50% increase in this procedure, which is marked by some striking regional variation,” from 5% of acute cholecystitis cases in the Northeast to less than 1% in some other regions. “This shows that as a group, we really don’t know what to do with this procedure.”
The revised Tokyo Guidelines for the management of acute cholangitis and cholecystitis aren’t hugely helpful either, noted Dr. Ackerman of the University of Pittsburgh Medical Center. While the guidelines are fairly straightforward for patients with grade 1 and grade 3 disease, “there’s a lot of gray area in grade 2.”
Treatment for these patients should include biliary drainage with antibiotics, but, he said, the recommendations for surgery, and whether it should be elective, immediate, or delayed, can be confusing for this group.
Dr. Ackerman’s retrospective analysis comprised 177 patients with acute cholecystitis who underwent an interval cholecystectomy (IC) after percutaneous cholecystostomy, and 227 controls who underwent an immediate cholecystectomy. The analysis spanned 2008-2013 and used data from seven hospitals in one health care system.
Patients who had the IC were older (70 vs. 55 years), had a worse American Society of Anesthesiologists class (3 vs. 2.5), and a worse Tokyo Grade (2 vs. 1).
Most of the IC procedures (119) were laparoscopic. There were 43 conversions to open and 15 were planned open surgeries. Among the immediate cholecystectomies, most (192) were laparoscopic. There were 28 conversions to open and six planned open surgeries.
The conversion rate was significantly higher among the IC group (28% vs.13%). The most common reasons for conversion were hostile abdomen (48% vs. 16%) and hostile right upper quadrant (34% vs. 58%).
Operating time was significantly longer in the IC group (121 vs. 90 minutes). Estimated blood loss was also significantly higher (30 vs. 15 cc). Total hospital stay was significantly longer (7 vs. 5 days), as was ICU stay (1 vs. 0.1 day).
There were no biliary tract injuries in the cholecystectomy group, while 5.7% of IC patients sustained such an injury. Bowel injuries, most often serosal, were also more common in the IC group (6% vs. 0.4%). The IC group had more surgical site infections as well (12% vs. 0.44%).
There was no significant difference in 30-day mortality, but at 1 year, IC patients were significantly more likely to have died (15% vs. 0.44%).
The ongoing CHOCOLATE trial (Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy) may help clarify the issue further, Dr. Ackerman said. The study being conducted in the Netherlands is randomizing high-risk cholecystitis patients to either laparoscopic cholecystectomy or percutaneous drainage.
Dr. Ackerman had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
HOLLYWOOD, FLA – Interval cholecystectomy remains a challenging procedure, with longer operative times and ICU stays, greater blood loss, more biliary and bowel injuries, and even hints of increased mortality, compared with immediate cholecystectomy, according to the findings from a retrospective study of 404 patients.
The staged procedure, completed after antibiotic therapy and percutaneous cholecystostomy, has been increasing in frequency over the past 10 years, but has not been rigorously studied, James Ackerman, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.
“Looking at Medicare data over the past decade, we see a 50% increase in this procedure, which is marked by some striking regional variation,” from 5% of acute cholecystitis cases in the Northeast to less than 1% in some other regions. “This shows that as a group, we really don’t know what to do with this procedure.”
The revised Tokyo Guidelines for the management of acute cholangitis and cholecystitis aren’t hugely helpful either, noted Dr. Ackerman of the University of Pittsburgh Medical Center. While the guidelines are fairly straightforward for patients with grade 1 and grade 3 disease, “there’s a lot of gray area in grade 2.”
Treatment for these patients should include biliary drainage with antibiotics, but, he said, the recommendations for surgery, and whether it should be elective, immediate, or delayed, can be confusing for this group.
Dr. Ackerman’s retrospective analysis comprised 177 patients with acute cholecystitis who underwent an interval cholecystectomy (IC) after percutaneous cholecystostomy, and 227 controls who underwent an immediate cholecystectomy. The analysis spanned 2008-2013 and used data from seven hospitals in one health care system.
Patients who had the IC were older (70 vs. 55 years), had a worse American Society of Anesthesiologists class (3 vs. 2.5), and a worse Tokyo Grade (2 vs. 1).
Most of the IC procedures (119) were laparoscopic. There were 43 conversions to open and 15 were planned open surgeries. Among the immediate cholecystectomies, most (192) were laparoscopic. There were 28 conversions to open and six planned open surgeries.
The conversion rate was significantly higher among the IC group (28% vs.13%). The most common reasons for conversion were hostile abdomen (48% vs. 16%) and hostile right upper quadrant (34% vs. 58%).
Operating time was significantly longer in the IC group (121 vs. 90 minutes). Estimated blood loss was also significantly higher (30 vs. 15 cc). Total hospital stay was significantly longer (7 vs. 5 days), as was ICU stay (1 vs. 0.1 day).
There were no biliary tract injuries in the cholecystectomy group, while 5.7% of IC patients sustained such an injury. Bowel injuries, most often serosal, were also more common in the IC group (6% vs. 0.4%). The IC group had more surgical site infections as well (12% vs. 0.44%).
There was no significant difference in 30-day mortality, but at 1 year, IC patients were significantly more likely to have died (15% vs. 0.44%).
The ongoing CHOCOLATE trial (Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy) may help clarify the issue further, Dr. Ackerman said. The study being conducted in the Netherlands is randomizing high-risk cholecystitis patients to either laparoscopic cholecystectomy or percutaneous drainage.
Dr. Ackerman had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
AT THE EAST ANNUAL SCIENTIFIC ASSEMBLY
Key clinical point:
Major finding: Interval cholecystectomy was associated with greater blood loss, more conversions to open surgery, bowel and biliary injuries, and even higher 1-year mortality (15% vs. 0.44%).
Data source: A retrospective review comparing 177 patients with interval surgery to 227 who had immediate surgery.
Disclosures: Dr. Ackerman had no financial disclosures.
Lysosomal acid lipase replacement corrects rare genetic cause of liver failure, atherosclerosis
BOSTON – Lysosomal acid lipase deficiency (LAL-D), a rare genetic cause of marked dyslipidemia that causes early multisystem organ damage, was effectively treated by a human recombinant enzyme to replace deficient lysosomal acid lipase, and the replacement enzyme was well tolerated over a 76-week trial.
LAL-D, when it begins in infancy, is usually fatal within the first year.
When LAL-D occurs later in life, it’s believed to be an “underappreciated cause of fibrosis, cirrhosis, severe dyslipidemia, and early-onset atherosclerosis,” according to Katryn Furuya, MD, and the coauthors of a poster presentation given at the annual meeting of the American Association for the Study of Liver Diseases.
Supplying the human recombinant lysosomal acid lipase, termed sebelipase alfa (SA), to children and adults with LAL-D over a 76-week period resulted in a reduction in alanine aminotransferase (ALT) for 98% of participants, normalization of ALT for 51% of participants, and normalization of aspartate aminotransferase (AST) levels for 65% of patients. Patients on SA also experienced reductions in serum triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and liver fat and total liver volume. “We’re basically replacing what they’re missing,” senior author Barbara Burton, MD, said in an interview.
“The target tissues that we want to get to are the liver, primarily, but also the spleen and the endothelial cells,” said Dr. Burton, professor of gastroenterology at Northwestern University, Chicago. “So the enzyme gets in and then it clears the accumulated fat, and that leads to a reduction in inflammation in the liver, because you don’t have these enlarged lysosomes that are irritating to the cells.”
The effects were seen in LAL-D patients participating in an open-label extension of a double-blind placebo-controlled trial of SA. Patients in the placebo arm who began receiving SA “experienced marked and sustained improvements in liver and lipid parameters, mirroring those observed in the SA group during the double-blind period,” wrote Dr. Furuya and her coauthors. Dr. Furuya, currently a pediatric gastroenterologist at the Mayo Clinic in Rochester, Minn., was a fellow at the Alfred I. duPont Hospital for Children, Wilmington, Del., at the time of the study.
The ARISE (Acid Lipase Replacement Investigating Safety and Efficacy) study included patients aged 4 years and older with a confirmed LAL-D diagnosis. They had to have a baseline ALT at least 1.5 times the upper limit of normal, and if taking lipid-lowering medications, they had to have been on a stable dose for at least 6 weeks before starting the study, and remain on the stable dose for at least the first 32 weeks of the study.
Patients with a history of hematopoietic or liver transplantation were excluded, as were those with severe liver dysfunction, indicated by a Child-Pugh score falling into class C.
The study began with 66 patients entering a randomized, double-blind, placebo-controlled study in which patients received an every-other-week intravenous infusion of SA 1 mg/kg (n = 36), or placebo (n = 30). Median age of participants was 13 years (range, 4-58 years).
After 22 weeks, this was followed by an open-label extension period, during which patients in both arms were unblinded and received SA 1 mg/kg for the duration of the study period; 65/66 patients entered this phase. This means that patients who were initially given SA during the blinded phase of the trial received a total of 76 weeks of SA, while patients who first received placebo before entering the open-label extension did not have their data analyzed until they had been on SA for a total of 78 weeks. The extra 2 weeks accounted for a crossover period for the placebo arm to enter the open-label phase.
The protocol allowed dose increases up to 3 mg/kg if patients’ AST, ALT, LDL-C, or TG levels remained elevated, or if patients under the age of 18 continued to have low weight-for-age z scores. For patients who had problems tolerating SA, the dose could be reduced to 0.35 kg/mg.
Efficacy outcome measures included the proportion of patients who achieved AST and ALT normalization, and those whose ALT values were reduced (but not necessarily normalized). Other measures included changes in LDL-C, HDL-C, non-HDL-C, and TG; reductions in hepatic fat content and total liver volume were also tracked.
After 76 weeks, LDL-C levels were reduced by a mean 27.5%, from 199 to 142 mg/dL, and non-HDL-C dropped by a mean 26.6%, from 230 to 166 mg/dL.
Liver volume and fat content was assessed by multiecho gradient echo magnetic resonance imaging (MEGE-MRI) performed at baseline, at week 20, and at study week 52, representing 52 weeks of SA treatment for the intervention arm and 30 weeks for the placebo arm of the initial trial.
After 52 weeks of SA exposure, the mean hepatic fat reduction was 20.5%, with 88% of patients having reduced liver fat. Of those with 30 weeks of SA exposure, 88% also had reduced liver fat, with a mean fat reduction of 28%.
Liver volume also dropped, by a mean of 13.2% for those with 52 weeks of SA exposure, with 90% of patients experiencing reduced liver volume. Patients with 30 weeks of SA treatment saw a mean 11.2% reduction in liver volume; 96% of this patient group saw some decrease in liver volume.
Safety outcomes included tracking treatment-emergent adverse events (TEAEs), as well as monitoring participants for anti-drug antibodies and for the development of neutralizing antibodies to SA. The safety outcome measures were assessed for patients with longer SA exposure, ranging from 86 to 152 weeks.
There were no patient discontinuations because of TEAEs, and most events were mild or moderate; the only serious adverse event considered related to treatment was an infusion-associated reaction. This patient was able to restart SA therapy after desensitization.
Anti-drug antibodies showed up in 11% of patients (n = 7), and two of these patients had neutralizing antibodies. The safety profile was not different for the group of patients testing positive for anti-drug antibodies, wrote Dr. Furuya and her coauthors.
Replacing LAL-D has promise for a population whose disease may go long undetected. “The patients are not obvious. They are difficult to diagnose,” said Dr. Burton. “They look normal, and they feel normal in many cases, until they have life-threatening disease,” such as end-stage liver disease or cardiovascular complications, she said. Even if elevated transaminases are found in routine screening, physicians are much more likely to think of the more-common nonalcoholic fatty liver disease (NAFLD) than LAL-D, said Dr. Burton, noting that an MRI won’t clarify the diagnosis, though a liver biopsy will show microvesicular rather than macrovesicular fat distribution in LAL-D.
When the clinical picture doesn’t fit with NAFLD, though, LAL-D should be in the differential, she said, adding that she suspects the actual incidence of LAL-D may be higher than has been reported in the literature.
Dr. Burton reported receiving research support, consulting fees, and honoraria from Alexion Pharmaceuticals – the study sponsor and manufacturer of sebelipase alfa. Dr. Furuya reported no disclosures.
[email protected]
On Twitter @karioakes
BOSTON – Lysosomal acid lipase deficiency (LAL-D), a rare genetic cause of marked dyslipidemia that causes early multisystem organ damage, was effectively treated by a human recombinant enzyme to replace deficient lysosomal acid lipase, and the replacement enzyme was well tolerated over a 76-week trial.
LAL-D, when it begins in infancy, is usually fatal within the first year.
When LAL-D occurs later in life, it’s believed to be an “underappreciated cause of fibrosis, cirrhosis, severe dyslipidemia, and early-onset atherosclerosis,” according to Katryn Furuya, MD, and the coauthors of a poster presentation given at the annual meeting of the American Association for the Study of Liver Diseases.
Supplying the human recombinant lysosomal acid lipase, termed sebelipase alfa (SA), to children and adults with LAL-D over a 76-week period resulted in a reduction in alanine aminotransferase (ALT) for 98% of participants, normalization of ALT for 51% of participants, and normalization of aspartate aminotransferase (AST) levels for 65% of patients. Patients on SA also experienced reductions in serum triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and liver fat and total liver volume. “We’re basically replacing what they’re missing,” senior author Barbara Burton, MD, said in an interview.
“The target tissues that we want to get to are the liver, primarily, but also the spleen and the endothelial cells,” said Dr. Burton, professor of gastroenterology at Northwestern University, Chicago. “So the enzyme gets in and then it clears the accumulated fat, and that leads to a reduction in inflammation in the liver, because you don’t have these enlarged lysosomes that are irritating to the cells.”
The effects were seen in LAL-D patients participating in an open-label extension of a double-blind placebo-controlled trial of SA. Patients in the placebo arm who began receiving SA “experienced marked and sustained improvements in liver and lipid parameters, mirroring those observed in the SA group during the double-blind period,” wrote Dr. Furuya and her coauthors. Dr. Furuya, currently a pediatric gastroenterologist at the Mayo Clinic in Rochester, Minn., was a fellow at the Alfred I. duPont Hospital for Children, Wilmington, Del., at the time of the study.
The ARISE (Acid Lipase Replacement Investigating Safety and Efficacy) study included patients aged 4 years and older with a confirmed LAL-D diagnosis. They had to have a baseline ALT at least 1.5 times the upper limit of normal, and if taking lipid-lowering medications, they had to have been on a stable dose for at least 6 weeks before starting the study, and remain on the stable dose for at least the first 32 weeks of the study.
Patients with a history of hematopoietic or liver transplantation were excluded, as were those with severe liver dysfunction, indicated by a Child-Pugh score falling into class C.
The study began with 66 patients entering a randomized, double-blind, placebo-controlled study in which patients received an every-other-week intravenous infusion of SA 1 mg/kg (n = 36), or placebo (n = 30). Median age of participants was 13 years (range, 4-58 years).
After 22 weeks, this was followed by an open-label extension period, during which patients in both arms were unblinded and received SA 1 mg/kg for the duration of the study period; 65/66 patients entered this phase. This means that patients who were initially given SA during the blinded phase of the trial received a total of 76 weeks of SA, while patients who first received placebo before entering the open-label extension did not have their data analyzed until they had been on SA for a total of 78 weeks. The extra 2 weeks accounted for a crossover period for the placebo arm to enter the open-label phase.
The protocol allowed dose increases up to 3 mg/kg if patients’ AST, ALT, LDL-C, or TG levels remained elevated, or if patients under the age of 18 continued to have low weight-for-age z scores. For patients who had problems tolerating SA, the dose could be reduced to 0.35 kg/mg.
Efficacy outcome measures included the proportion of patients who achieved AST and ALT normalization, and those whose ALT values were reduced (but not necessarily normalized). Other measures included changes in LDL-C, HDL-C, non-HDL-C, and TG; reductions in hepatic fat content and total liver volume were also tracked.
After 76 weeks, LDL-C levels were reduced by a mean 27.5%, from 199 to 142 mg/dL, and non-HDL-C dropped by a mean 26.6%, from 230 to 166 mg/dL.
Liver volume and fat content was assessed by multiecho gradient echo magnetic resonance imaging (MEGE-MRI) performed at baseline, at week 20, and at study week 52, representing 52 weeks of SA treatment for the intervention arm and 30 weeks for the placebo arm of the initial trial.
After 52 weeks of SA exposure, the mean hepatic fat reduction was 20.5%, with 88% of patients having reduced liver fat. Of those with 30 weeks of SA exposure, 88% also had reduced liver fat, with a mean fat reduction of 28%.
Liver volume also dropped, by a mean of 13.2% for those with 52 weeks of SA exposure, with 90% of patients experiencing reduced liver volume. Patients with 30 weeks of SA treatment saw a mean 11.2% reduction in liver volume; 96% of this patient group saw some decrease in liver volume.
Safety outcomes included tracking treatment-emergent adverse events (TEAEs), as well as monitoring participants for anti-drug antibodies and for the development of neutralizing antibodies to SA. The safety outcome measures were assessed for patients with longer SA exposure, ranging from 86 to 152 weeks.
There were no patient discontinuations because of TEAEs, and most events were mild or moderate; the only serious adverse event considered related to treatment was an infusion-associated reaction. This patient was able to restart SA therapy after desensitization.
Anti-drug antibodies showed up in 11% of patients (n = 7), and two of these patients had neutralizing antibodies. The safety profile was not different for the group of patients testing positive for anti-drug antibodies, wrote Dr. Furuya and her coauthors.
Replacing LAL-D has promise for a population whose disease may go long undetected. “The patients are not obvious. They are difficult to diagnose,” said Dr. Burton. “They look normal, and they feel normal in many cases, until they have life-threatening disease,” such as end-stage liver disease or cardiovascular complications, she said. Even if elevated transaminases are found in routine screening, physicians are much more likely to think of the more-common nonalcoholic fatty liver disease (NAFLD) than LAL-D, said Dr. Burton, noting that an MRI won’t clarify the diagnosis, though a liver biopsy will show microvesicular rather than macrovesicular fat distribution in LAL-D.
When the clinical picture doesn’t fit with NAFLD, though, LAL-D should be in the differential, she said, adding that she suspects the actual incidence of LAL-D may be higher than has been reported in the literature.
Dr. Burton reported receiving research support, consulting fees, and honoraria from Alexion Pharmaceuticals – the study sponsor and manufacturer of sebelipase alfa. Dr. Furuya reported no disclosures.
[email protected]
On Twitter @karioakes
BOSTON – Lysosomal acid lipase deficiency (LAL-D), a rare genetic cause of marked dyslipidemia that causes early multisystem organ damage, was effectively treated by a human recombinant enzyme to replace deficient lysosomal acid lipase, and the replacement enzyme was well tolerated over a 76-week trial.
LAL-D, when it begins in infancy, is usually fatal within the first year.
When LAL-D occurs later in life, it’s believed to be an “underappreciated cause of fibrosis, cirrhosis, severe dyslipidemia, and early-onset atherosclerosis,” according to Katryn Furuya, MD, and the coauthors of a poster presentation given at the annual meeting of the American Association for the Study of Liver Diseases.
Supplying the human recombinant lysosomal acid lipase, termed sebelipase alfa (SA), to children and adults with LAL-D over a 76-week period resulted in a reduction in alanine aminotransferase (ALT) for 98% of participants, normalization of ALT for 51% of participants, and normalization of aspartate aminotransferase (AST) levels for 65% of patients. Patients on SA also experienced reductions in serum triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and liver fat and total liver volume. “We’re basically replacing what they’re missing,” senior author Barbara Burton, MD, said in an interview.
“The target tissues that we want to get to are the liver, primarily, but also the spleen and the endothelial cells,” said Dr. Burton, professor of gastroenterology at Northwestern University, Chicago. “So the enzyme gets in and then it clears the accumulated fat, and that leads to a reduction in inflammation in the liver, because you don’t have these enlarged lysosomes that are irritating to the cells.”
The effects were seen in LAL-D patients participating in an open-label extension of a double-blind placebo-controlled trial of SA. Patients in the placebo arm who began receiving SA “experienced marked and sustained improvements in liver and lipid parameters, mirroring those observed in the SA group during the double-blind period,” wrote Dr. Furuya and her coauthors. Dr. Furuya, currently a pediatric gastroenterologist at the Mayo Clinic in Rochester, Minn., was a fellow at the Alfred I. duPont Hospital for Children, Wilmington, Del., at the time of the study.
The ARISE (Acid Lipase Replacement Investigating Safety and Efficacy) study included patients aged 4 years and older with a confirmed LAL-D diagnosis. They had to have a baseline ALT at least 1.5 times the upper limit of normal, and if taking lipid-lowering medications, they had to have been on a stable dose for at least 6 weeks before starting the study, and remain on the stable dose for at least the first 32 weeks of the study.
Patients with a history of hematopoietic or liver transplantation were excluded, as were those with severe liver dysfunction, indicated by a Child-Pugh score falling into class C.
The study began with 66 patients entering a randomized, double-blind, placebo-controlled study in which patients received an every-other-week intravenous infusion of SA 1 mg/kg (n = 36), or placebo (n = 30). Median age of participants was 13 years (range, 4-58 years).
After 22 weeks, this was followed by an open-label extension period, during which patients in both arms were unblinded and received SA 1 mg/kg for the duration of the study period; 65/66 patients entered this phase. This means that patients who were initially given SA during the blinded phase of the trial received a total of 76 weeks of SA, while patients who first received placebo before entering the open-label extension did not have their data analyzed until they had been on SA for a total of 78 weeks. The extra 2 weeks accounted for a crossover period for the placebo arm to enter the open-label phase.
The protocol allowed dose increases up to 3 mg/kg if patients’ AST, ALT, LDL-C, or TG levels remained elevated, or if patients under the age of 18 continued to have low weight-for-age z scores. For patients who had problems tolerating SA, the dose could be reduced to 0.35 kg/mg.
Efficacy outcome measures included the proportion of patients who achieved AST and ALT normalization, and those whose ALT values were reduced (but not necessarily normalized). Other measures included changes in LDL-C, HDL-C, non-HDL-C, and TG; reductions in hepatic fat content and total liver volume were also tracked.
After 76 weeks, LDL-C levels were reduced by a mean 27.5%, from 199 to 142 mg/dL, and non-HDL-C dropped by a mean 26.6%, from 230 to 166 mg/dL.
Liver volume and fat content was assessed by multiecho gradient echo magnetic resonance imaging (MEGE-MRI) performed at baseline, at week 20, and at study week 52, representing 52 weeks of SA treatment for the intervention arm and 30 weeks for the placebo arm of the initial trial.
After 52 weeks of SA exposure, the mean hepatic fat reduction was 20.5%, with 88% of patients having reduced liver fat. Of those with 30 weeks of SA exposure, 88% also had reduced liver fat, with a mean fat reduction of 28%.
Liver volume also dropped, by a mean of 13.2% for those with 52 weeks of SA exposure, with 90% of patients experiencing reduced liver volume. Patients with 30 weeks of SA treatment saw a mean 11.2% reduction in liver volume; 96% of this patient group saw some decrease in liver volume.
Safety outcomes included tracking treatment-emergent adverse events (TEAEs), as well as monitoring participants for anti-drug antibodies and for the development of neutralizing antibodies to SA. The safety outcome measures were assessed for patients with longer SA exposure, ranging from 86 to 152 weeks.
There were no patient discontinuations because of TEAEs, and most events were mild or moderate; the only serious adverse event considered related to treatment was an infusion-associated reaction. This patient was able to restart SA therapy after desensitization.
Anti-drug antibodies showed up in 11% of patients (n = 7), and two of these patients had neutralizing antibodies. The safety profile was not different for the group of patients testing positive for anti-drug antibodies, wrote Dr. Furuya and her coauthors.
Replacing LAL-D has promise for a population whose disease may go long undetected. “The patients are not obvious. They are difficult to diagnose,” said Dr. Burton. “They look normal, and they feel normal in many cases, until they have life-threatening disease,” such as end-stage liver disease or cardiovascular complications, she said. Even if elevated transaminases are found in routine screening, physicians are much more likely to think of the more-common nonalcoholic fatty liver disease (NAFLD) than LAL-D, said Dr. Burton, noting that an MRI won’t clarify the diagnosis, though a liver biopsy will show microvesicular rather than macrovesicular fat distribution in LAL-D.
When the clinical picture doesn’t fit with NAFLD, though, LAL-D should be in the differential, she said, adding that she suspects the actual incidence of LAL-D may be higher than has been reported in the literature.
Dr. Burton reported receiving research support, consulting fees, and honoraria from Alexion Pharmaceuticals – the study sponsor and manufacturer of sebelipase alfa. Dr. Furuya reported no disclosures.
[email protected]
On Twitter @karioakes
AT THE LIVER MEETING 2016
Key clinical point:
Major finding: Of patients with LAL-D who received sebelipase alfa (recombinant LAL), 51% experienced normalization of ALT, and 65% had normalization of AST.
Data source: Open-label extension of randomized, double-blind, placebo-controlled trial of 66 patients with LAL-D.
Disclosures: Dr. Burton reported receiving research support, consulting fees, and honoraria from Alexion Pharmaceuticals – the study sponsor and manufacturer of sebelipase alfa. Dr. Furuya reported no disclosures.
VIDEO: Protein-rich diet can help manage type 2 diabetes, NAFLD
Patients with type 2 diabetes should be put on diets rich in either animal or plant protein to reduce not only liver fat, but insulin resistance and hepatic necroinflammation markers as well, according to a study published in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.10.007).
“High-protein diets have shown variable and sometimes even favorable effects on glucose metabolism and insulin sensitivity in people with type 2 diabetes and it is unclear which metabolic pathways are involved,” wrote the authors of the study, led by Mariya Markova, MD, of the German Institute of Human Nutrition Potsdam-Rehbrücke in Nuthetal, Germany.
SOURCE: American Gastroenterological Association
Obesity and insulin resistance have long been linked to liver fat, with excessive amounts of the latter causing nonalcoholic fatty liver disease (NAFLD), with a significant risk of nonalcoholic steatohepatitis (NASH) developing as well. Compounding this issue, at least in the United States, are widespread dietary and nutritional habits that promote consumption of animal protein, carbohydrates, and saturated fats. This “hypercaloric Western style diet,” as the authors call it, exacerbates the accumulation of fat deposits in the liver and complicates the health of patients across the country, regardless of weight.
“Remarkably, diets restricted in methionine were shown to prevent the development of insulin resistance and of the metabolic syndrome in animal models [so] the type of protein may elicit different metabolic responses depending on the amino acid composition,” Dr. Markova and her coinvestigators noted. “It is therefore hypothesized that high-plant-protein diets exert favorable effects on hepatic fat content and metabolic responses as compared to high intake of animal protein rich in BCAA [branched-chain amino acids] and methionine,” both of which can be found in suitably low levels via plant protein.
Dr. Markova and her team devised a prospective, randomized, open-label clinical trial involving 44 patients with type 2 diabetes and NAFLD, all of whom were recruited at the department of clinical nutrition of the German Institute of Human Nutrition Potsdam-Rehbrücke between June 2013 and March 2015. Subjects were randomized into one of two cohorts, each of which were assigned a diet rich in either animal protein (AP) or plant protein (PP) for a period of 6 weeks. Median body mass index in the AP cohort was 31.0 ± 0.8, and was 29.4 ± 1.0 in the PP cohort.
The AP cohort diet consisted mainly of meat and dairy products, while legumes constituted the bulk of the PP cohort diet. Both diets were isocaloric and had the same macronutrient makeup: 30% protein, 40% carbohydrates, and 30% fat. Seven subjects dropped out prior to completion of the study; of the 37 that remained all the way through – 19 in the AP cohort, 18 in the PP cohort – the age range was 49-78 years. Subjects maintained the same physical exercise regimens throughout the study that they had beforehand, and were asked not to alter them. Hemoglobin A1c levels ranged from 5.8% to 8.8% at baseline, and evaluations were carried out at fasting levels for each subject.
Patients in both cohorts saw significant decreases in intrahepatic fat content by the end of the trial period. Those in the AP cohort saw decreases of 48.0% (P = .0002), while those in the PP cohort saw a decrease of 35.7% (P = .001). Perhaps most importantly, the reductions in both cohorts were not correlated to body weight. In addition, levels of fibroblast growth factor 21 (FGF21), which has been shown to be a predictive marker of NAFLD, decreased by nearly 50% for both AP and PP cohorts (P less than .0002 for both).
“Despite the elevated intake and postprandial uptake of methionine and BCAA in the AP group, there was no indication of negative effects of these components,” the authors stated in the study. “The origin of protein – animal or plant – did not play a major role. Both high-protein diets unexpectedly induced strong reductions of FGF21, which was associated with metabolic improvements and the decrease of IHL.”
Despite these findings, however, the 6-week time span used here is not sufficient to determine just how viable this diet may be in the long term, according to the authors. Further studies will be needed, and will need to take place over longer periods of time, to “show the durability of the responses and eventual adverse effects of the diets.” Furthermore, different age groups must be examined to find out if the benefits observed by Dr. Markova and her coinvestigators were somehow related to the age of these subjects.
The study was funded by grants from German Federal Ministry of Food and Agriculture and German Center for Diabetes Research. Dr. Markova and her coauthors did not report any financial disclosures.
Human studies to assess the effects of isocaloric macronutrient substitution are fraught with difficulty. If one macronutrient is increased, what happens to the others? If you observe an effect, is it the phenomenon you were seeking due to the macronutrient you altered, or an epiphenomenon due to changes in the others?
Markova et al. attempted to study a 6-week “isocaloric” increase of animal vs. plant protein (from 17% to 30% of calories as protein). However, a decrease of percent fat from 41% to 30%, and a reduction in carbohydrate from 42% to 40% occurred commensurately. This brings up three concerns. First, despite the diet’s being “isocaloric,” weight and body mass index decreased by 2 kg and 0.8 kg/m2, respectively. Reductions in intrahepatic, visceral, and subcutaneous fat, and an increase in lean body mass were noted. So was the diet isocaloric? Protein reduces plasma ghrelin levels and is more satiating. Furthermore, metabolism of protein to ATP is inefficient compared to that of carbohydrate or fat. The authors say only that calories were “unrestricted.” These issues do not engender “isocaloric” confidence.
Lastly, the type of carbohydrate was not controlled for. Fructose is significantly more lipogenic than glucose. Yet they were lumped together as “carbohydrate,” and were uncontrolled. So what macronutrient really caused the reduction in liver fat? These methodological issues detract from the author’s message, and this study must be considered preliminary.
Robert H. Lustig, MD, MSL, is in the division of pediatric endocrinology, UCSF Benioff Children’s Hospital, San Francisco; member, UCSF Institute for Health Policy Studies. Dr. Lustig declared no conflicts of interest.
Human studies to assess the effects of isocaloric macronutrient substitution are fraught with difficulty. If one macronutrient is increased, what happens to the others? If you observe an effect, is it the phenomenon you were seeking due to the macronutrient you altered, or an epiphenomenon due to changes in the others?
Markova et al. attempted to study a 6-week “isocaloric” increase of animal vs. plant protein (from 17% to 30% of calories as protein). However, a decrease of percent fat from 41% to 30%, and a reduction in carbohydrate from 42% to 40% occurred commensurately. This brings up three concerns. First, despite the diet’s being “isocaloric,” weight and body mass index decreased by 2 kg and 0.8 kg/m2, respectively. Reductions in intrahepatic, visceral, and subcutaneous fat, and an increase in lean body mass were noted. So was the diet isocaloric? Protein reduces plasma ghrelin levels and is more satiating. Furthermore, metabolism of protein to ATP is inefficient compared to that of carbohydrate or fat. The authors say only that calories were “unrestricted.” These issues do not engender “isocaloric” confidence.
Lastly, the type of carbohydrate was not controlled for. Fructose is significantly more lipogenic than glucose. Yet they were lumped together as “carbohydrate,” and were uncontrolled. So what macronutrient really caused the reduction in liver fat? These methodological issues detract from the author’s message, and this study must be considered preliminary.
Robert H. Lustig, MD, MSL, is in the division of pediatric endocrinology, UCSF Benioff Children’s Hospital, San Francisco; member, UCSF Institute for Health Policy Studies. Dr. Lustig declared no conflicts of interest.
Human studies to assess the effects of isocaloric macronutrient substitution are fraught with difficulty. If one macronutrient is increased, what happens to the others? If you observe an effect, is it the phenomenon you were seeking due to the macronutrient you altered, or an epiphenomenon due to changes in the others?
Markova et al. attempted to study a 6-week “isocaloric” increase of animal vs. plant protein (from 17% to 30% of calories as protein). However, a decrease of percent fat from 41% to 30%, and a reduction in carbohydrate from 42% to 40% occurred commensurately. This brings up three concerns. First, despite the diet’s being “isocaloric,” weight and body mass index decreased by 2 kg and 0.8 kg/m2, respectively. Reductions in intrahepatic, visceral, and subcutaneous fat, and an increase in lean body mass were noted. So was the diet isocaloric? Protein reduces plasma ghrelin levels and is more satiating. Furthermore, metabolism of protein to ATP is inefficient compared to that of carbohydrate or fat. The authors say only that calories were “unrestricted.” These issues do not engender “isocaloric” confidence.
Lastly, the type of carbohydrate was not controlled for. Fructose is significantly more lipogenic than glucose. Yet they were lumped together as “carbohydrate,” and were uncontrolled. So what macronutrient really caused the reduction in liver fat? These methodological issues detract from the author’s message, and this study must be considered preliminary.
Robert H. Lustig, MD, MSL, is in the division of pediatric endocrinology, UCSF Benioff Children’s Hospital, San Francisco; member, UCSF Institute for Health Policy Studies. Dr. Lustig declared no conflicts of interest.
Patients with type 2 diabetes should be put on diets rich in either animal or plant protein to reduce not only liver fat, but insulin resistance and hepatic necroinflammation markers as well, according to a study published in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.10.007).
“High-protein diets have shown variable and sometimes even favorable effects on glucose metabolism and insulin sensitivity in people with type 2 diabetes and it is unclear which metabolic pathways are involved,” wrote the authors of the study, led by Mariya Markova, MD, of the German Institute of Human Nutrition Potsdam-Rehbrücke in Nuthetal, Germany.
SOURCE: American Gastroenterological Association
Obesity and insulin resistance have long been linked to liver fat, with excessive amounts of the latter causing nonalcoholic fatty liver disease (NAFLD), with a significant risk of nonalcoholic steatohepatitis (NASH) developing as well. Compounding this issue, at least in the United States, are widespread dietary and nutritional habits that promote consumption of animal protein, carbohydrates, and saturated fats. This “hypercaloric Western style diet,” as the authors call it, exacerbates the accumulation of fat deposits in the liver and complicates the health of patients across the country, regardless of weight.
“Remarkably, diets restricted in methionine were shown to prevent the development of insulin resistance and of the metabolic syndrome in animal models [so] the type of protein may elicit different metabolic responses depending on the amino acid composition,” Dr. Markova and her coinvestigators noted. “It is therefore hypothesized that high-plant-protein diets exert favorable effects on hepatic fat content and metabolic responses as compared to high intake of animal protein rich in BCAA [branched-chain amino acids] and methionine,” both of which can be found in suitably low levels via plant protein.
Dr. Markova and her team devised a prospective, randomized, open-label clinical trial involving 44 patients with type 2 diabetes and NAFLD, all of whom were recruited at the department of clinical nutrition of the German Institute of Human Nutrition Potsdam-Rehbrücke between June 2013 and March 2015. Subjects were randomized into one of two cohorts, each of which were assigned a diet rich in either animal protein (AP) or plant protein (PP) for a period of 6 weeks. Median body mass index in the AP cohort was 31.0 ± 0.8, and was 29.4 ± 1.0 in the PP cohort.
The AP cohort diet consisted mainly of meat and dairy products, while legumes constituted the bulk of the PP cohort diet. Both diets were isocaloric and had the same macronutrient makeup: 30% protein, 40% carbohydrates, and 30% fat. Seven subjects dropped out prior to completion of the study; of the 37 that remained all the way through – 19 in the AP cohort, 18 in the PP cohort – the age range was 49-78 years. Subjects maintained the same physical exercise regimens throughout the study that they had beforehand, and were asked not to alter them. Hemoglobin A1c levels ranged from 5.8% to 8.8% at baseline, and evaluations were carried out at fasting levels for each subject.
Patients in both cohorts saw significant decreases in intrahepatic fat content by the end of the trial period. Those in the AP cohort saw decreases of 48.0% (P = .0002), while those in the PP cohort saw a decrease of 35.7% (P = .001). Perhaps most importantly, the reductions in both cohorts were not correlated to body weight. In addition, levels of fibroblast growth factor 21 (FGF21), which has been shown to be a predictive marker of NAFLD, decreased by nearly 50% for both AP and PP cohorts (P less than .0002 for both).
“Despite the elevated intake and postprandial uptake of methionine and BCAA in the AP group, there was no indication of negative effects of these components,” the authors stated in the study. “The origin of protein – animal or plant – did not play a major role. Both high-protein diets unexpectedly induced strong reductions of FGF21, which was associated with metabolic improvements and the decrease of IHL.”
Despite these findings, however, the 6-week time span used here is not sufficient to determine just how viable this diet may be in the long term, according to the authors. Further studies will be needed, and will need to take place over longer periods of time, to “show the durability of the responses and eventual adverse effects of the diets.” Furthermore, different age groups must be examined to find out if the benefits observed by Dr. Markova and her coinvestigators were somehow related to the age of these subjects.
The study was funded by grants from German Federal Ministry of Food and Agriculture and German Center for Diabetes Research. Dr. Markova and her coauthors did not report any financial disclosures.
Patients with type 2 diabetes should be put on diets rich in either animal or plant protein to reduce not only liver fat, but insulin resistance and hepatic necroinflammation markers as well, according to a study published in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.10.007).
“High-protein diets have shown variable and sometimes even favorable effects on glucose metabolism and insulin sensitivity in people with type 2 diabetes and it is unclear which metabolic pathways are involved,” wrote the authors of the study, led by Mariya Markova, MD, of the German Institute of Human Nutrition Potsdam-Rehbrücke in Nuthetal, Germany.
SOURCE: American Gastroenterological Association
Obesity and insulin resistance have long been linked to liver fat, with excessive amounts of the latter causing nonalcoholic fatty liver disease (NAFLD), with a significant risk of nonalcoholic steatohepatitis (NASH) developing as well. Compounding this issue, at least in the United States, are widespread dietary and nutritional habits that promote consumption of animal protein, carbohydrates, and saturated fats. This “hypercaloric Western style diet,” as the authors call it, exacerbates the accumulation of fat deposits in the liver and complicates the health of patients across the country, regardless of weight.
“Remarkably, diets restricted in methionine were shown to prevent the development of insulin resistance and of the metabolic syndrome in animal models [so] the type of protein may elicit different metabolic responses depending on the amino acid composition,” Dr. Markova and her coinvestigators noted. “It is therefore hypothesized that high-plant-protein diets exert favorable effects on hepatic fat content and metabolic responses as compared to high intake of animal protein rich in BCAA [branched-chain amino acids] and methionine,” both of which can be found in suitably low levels via plant protein.
Dr. Markova and her team devised a prospective, randomized, open-label clinical trial involving 44 patients with type 2 diabetes and NAFLD, all of whom were recruited at the department of clinical nutrition of the German Institute of Human Nutrition Potsdam-Rehbrücke between June 2013 and March 2015. Subjects were randomized into one of two cohorts, each of which were assigned a diet rich in either animal protein (AP) or plant protein (PP) for a period of 6 weeks. Median body mass index in the AP cohort was 31.0 ± 0.8, and was 29.4 ± 1.0 in the PP cohort.
The AP cohort diet consisted mainly of meat and dairy products, while legumes constituted the bulk of the PP cohort diet. Both diets were isocaloric and had the same macronutrient makeup: 30% protein, 40% carbohydrates, and 30% fat. Seven subjects dropped out prior to completion of the study; of the 37 that remained all the way through – 19 in the AP cohort, 18 in the PP cohort – the age range was 49-78 years. Subjects maintained the same physical exercise regimens throughout the study that they had beforehand, and were asked not to alter them. Hemoglobin A1c levels ranged from 5.8% to 8.8% at baseline, and evaluations were carried out at fasting levels for each subject.
Patients in both cohorts saw significant decreases in intrahepatic fat content by the end of the trial period. Those in the AP cohort saw decreases of 48.0% (P = .0002), while those in the PP cohort saw a decrease of 35.7% (P = .001). Perhaps most importantly, the reductions in both cohorts were not correlated to body weight. In addition, levels of fibroblast growth factor 21 (FGF21), which has been shown to be a predictive marker of NAFLD, decreased by nearly 50% for both AP and PP cohorts (P less than .0002 for both).
“Despite the elevated intake and postprandial uptake of methionine and BCAA in the AP group, there was no indication of negative effects of these components,” the authors stated in the study. “The origin of protein – animal or plant – did not play a major role. Both high-protein diets unexpectedly induced strong reductions of FGF21, which was associated with metabolic improvements and the decrease of IHL.”
Despite these findings, however, the 6-week time span used here is not sufficient to determine just how viable this diet may be in the long term, according to the authors. Further studies will be needed, and will need to take place over longer periods of time, to “show the durability of the responses and eventual adverse effects of the diets.” Furthermore, different age groups must be examined to find out if the benefits observed by Dr. Markova and her coinvestigators were somehow related to the age of these subjects.
The study was funded by grants from German Federal Ministry of Food and Agriculture and German Center for Diabetes Research. Dr. Markova and her coauthors did not report any financial disclosures.
FROM GASTROENTEROLOGY
Key clinical point:
Major finding: Animal- and plant-protein diets reduced liver fat for type 2 diabetes patients by 36%-48% over the course of 6 months (P = .0002 and P = .001, respectively).
Data source: Prospective study of 37 type 2 diabetes patients from June 2013 to March 2015.
Disclosures: The German Federal Ministry of Food and Agriculture and German Center for Diabetes Research supported the study. The authors did not report any financial disclosures.
AGA Clinical Practice Update: Treatment for severe alcohol hepatitis challenging
Acute alcoholic hepatitis carries a high risk of mortality, yet only a minority of patients admitted to the hospital with the condition receive appropriate treatment, said the authors of an expert review.
Writing in the January 2017 issue of Clinical Gastroenterology and Hepatology, Mack C. Mitchell Jr., MD, of the University of Texas Southwestern Medical Center, Dallas, and Craig J. McClain, MD, of the University of Louisville (Ky.), described the challenges associated with treating acute alcoholic hepatitis and its consequences.
Acute alcohol hepatitis develops in heavy drinkers and presents with rapid onset of malaise, anorexia, tender hepatomegaly, and features of the systemic inflammatory response syndrome. Patients with alcoholic hepatitis also are at high risk of nutritional deficiency, infection, acute kidney injury, and multiorgan failure.
The two most widely used therapies are glucocorticoids – generally considered the standard of care for severe alcoholic hepatitis – and the phosphodiesterase inhibitor pentoxifylline (Clin Gastroenterol Hepatol. 2017. doi: 10.1016/j.cgh.2016.08.047).
“Although in its most severe form AH has a high short-term mortality rate if untreated, in 2011, only 28% of more than 1,600 patients admitted to U.S. hospitals were treated with glucocorticoids and 17% with pentoxifylline (PTX), suggesting a lack of widespread confidence in the two most frequently used therapies for AH,” the authors wrote.
Both drugs work by addressing the underlying inflammation that plays a key role in liver injury, but the evidence for both is mixed: A 2008 Cochrane systematic review of 15 trials concluded there was no benefit from glucocorticoids, largely because of substantial variability in bias across the trials, while two meta-analyses of pentoxifylline trials concluded that there were no differences in short-term mortality between those who received it and those who did not.
Some patients are unsuitable for glucocorticoids and others may develop resistance. There is also the possibility that, while glucocorticoids may improve short-term survival, the associated increase in infection risk removes that advantage at 90 days and 1 year after diagnosis. These infections, in turn, often precede the development of acute kidney injury and multiorgan failure.
The authors, however, did suggest that the approach of very high, short-term bursts of glucocorticoids to induce “immune paralysis” – an approach taken for lupus nephritis – might be considered.
They stressed that abstinence was the cornerstone of treatment for acute alcoholic hepatitis, with studies showing that patients with alcoholic hepatitis who resume heavy drinking have significantly worse outcomes than those who don’t.
“Although abstinence is important at all stages, it is particularly important to emphasize abstinence beyond 90 days when many patients are regaining normal functioning,” Dr. Mitchell and Dr. McClain wrote.
Infection, kidney injury, and malnutrition are all significant concerns in patients with acute alcoholic hepatitis.
With respect to infection, the authors said considerable suspicion is required to pick up bacterial and fungal infections, as patients may not always have a fever and an elevated white blood cell count is an unreliable indicator. Infection also can lead to acute kidney injury.
Malnutrition is not only common in patients with alcohol hepatitis, but it has a significant negative impact on recovery. All patients should be encouraged to meet nutritional goals as early as possible, but just how to achieve this is controversial, the authors stressed.
For example, one study suggested that enteral nutrition was as good as glucocorticoids in reducing 28-day mortality, while another found enteral nutrition via nasogastric tube – in addition to glucocorticoids – was no better than glucocorticoids alone. “Whether [nasogastric] tubes should be used to provide enteral nutrition is a subject of controversy,” the authors wrote. “Normal- to high-protein diets are safe and do not increase the risk of encephalopathy in patients with AH.”
No conflicts of interest were declared.
Acute alcoholic hepatitis carries a high risk of mortality, yet only a minority of patients admitted to the hospital with the condition receive appropriate treatment, said the authors of an expert review.
Writing in the January 2017 issue of Clinical Gastroenterology and Hepatology, Mack C. Mitchell Jr., MD, of the University of Texas Southwestern Medical Center, Dallas, and Craig J. McClain, MD, of the University of Louisville (Ky.), described the challenges associated with treating acute alcoholic hepatitis and its consequences.
Acute alcohol hepatitis develops in heavy drinkers and presents with rapid onset of malaise, anorexia, tender hepatomegaly, and features of the systemic inflammatory response syndrome. Patients with alcoholic hepatitis also are at high risk of nutritional deficiency, infection, acute kidney injury, and multiorgan failure.
The two most widely used therapies are glucocorticoids – generally considered the standard of care for severe alcoholic hepatitis – and the phosphodiesterase inhibitor pentoxifylline (Clin Gastroenterol Hepatol. 2017. doi: 10.1016/j.cgh.2016.08.047).
“Although in its most severe form AH has a high short-term mortality rate if untreated, in 2011, only 28% of more than 1,600 patients admitted to U.S. hospitals were treated with glucocorticoids and 17% with pentoxifylline (PTX), suggesting a lack of widespread confidence in the two most frequently used therapies for AH,” the authors wrote.
Both drugs work by addressing the underlying inflammation that plays a key role in liver injury, but the evidence for both is mixed: A 2008 Cochrane systematic review of 15 trials concluded there was no benefit from glucocorticoids, largely because of substantial variability in bias across the trials, while two meta-analyses of pentoxifylline trials concluded that there were no differences in short-term mortality between those who received it and those who did not.
Some patients are unsuitable for glucocorticoids and others may develop resistance. There is also the possibility that, while glucocorticoids may improve short-term survival, the associated increase in infection risk removes that advantage at 90 days and 1 year after diagnosis. These infections, in turn, often precede the development of acute kidney injury and multiorgan failure.
The authors, however, did suggest that the approach of very high, short-term bursts of glucocorticoids to induce “immune paralysis” – an approach taken for lupus nephritis – might be considered.
They stressed that abstinence was the cornerstone of treatment for acute alcoholic hepatitis, with studies showing that patients with alcoholic hepatitis who resume heavy drinking have significantly worse outcomes than those who don’t.
“Although abstinence is important at all stages, it is particularly important to emphasize abstinence beyond 90 days when many patients are regaining normal functioning,” Dr. Mitchell and Dr. McClain wrote.
Infection, kidney injury, and malnutrition are all significant concerns in patients with acute alcoholic hepatitis.
With respect to infection, the authors said considerable suspicion is required to pick up bacterial and fungal infections, as patients may not always have a fever and an elevated white blood cell count is an unreliable indicator. Infection also can lead to acute kidney injury.
Malnutrition is not only common in patients with alcohol hepatitis, but it has a significant negative impact on recovery. All patients should be encouraged to meet nutritional goals as early as possible, but just how to achieve this is controversial, the authors stressed.
For example, one study suggested that enteral nutrition was as good as glucocorticoids in reducing 28-day mortality, while another found enteral nutrition via nasogastric tube – in addition to glucocorticoids – was no better than glucocorticoids alone. “Whether [nasogastric] tubes should be used to provide enteral nutrition is a subject of controversy,” the authors wrote. “Normal- to high-protein diets are safe and do not increase the risk of encephalopathy in patients with AH.”
No conflicts of interest were declared.
Acute alcoholic hepatitis carries a high risk of mortality, yet only a minority of patients admitted to the hospital with the condition receive appropriate treatment, said the authors of an expert review.
Writing in the January 2017 issue of Clinical Gastroenterology and Hepatology, Mack C. Mitchell Jr., MD, of the University of Texas Southwestern Medical Center, Dallas, and Craig J. McClain, MD, of the University of Louisville (Ky.), described the challenges associated with treating acute alcoholic hepatitis and its consequences.
Acute alcohol hepatitis develops in heavy drinkers and presents with rapid onset of malaise, anorexia, tender hepatomegaly, and features of the systemic inflammatory response syndrome. Patients with alcoholic hepatitis also are at high risk of nutritional deficiency, infection, acute kidney injury, and multiorgan failure.
The two most widely used therapies are glucocorticoids – generally considered the standard of care for severe alcoholic hepatitis – and the phosphodiesterase inhibitor pentoxifylline (Clin Gastroenterol Hepatol. 2017. doi: 10.1016/j.cgh.2016.08.047).
“Although in its most severe form AH has a high short-term mortality rate if untreated, in 2011, only 28% of more than 1,600 patients admitted to U.S. hospitals were treated with glucocorticoids and 17% with pentoxifylline (PTX), suggesting a lack of widespread confidence in the two most frequently used therapies for AH,” the authors wrote.
Both drugs work by addressing the underlying inflammation that plays a key role in liver injury, but the evidence for both is mixed: A 2008 Cochrane systematic review of 15 trials concluded there was no benefit from glucocorticoids, largely because of substantial variability in bias across the trials, while two meta-analyses of pentoxifylline trials concluded that there were no differences in short-term mortality between those who received it and those who did not.
Some patients are unsuitable for glucocorticoids and others may develop resistance. There is also the possibility that, while glucocorticoids may improve short-term survival, the associated increase in infection risk removes that advantage at 90 days and 1 year after diagnosis. These infections, in turn, often precede the development of acute kidney injury and multiorgan failure.
The authors, however, did suggest that the approach of very high, short-term bursts of glucocorticoids to induce “immune paralysis” – an approach taken for lupus nephritis – might be considered.
They stressed that abstinence was the cornerstone of treatment for acute alcoholic hepatitis, with studies showing that patients with alcoholic hepatitis who resume heavy drinking have significantly worse outcomes than those who don’t.
“Although abstinence is important at all stages, it is particularly important to emphasize abstinence beyond 90 days when many patients are regaining normal functioning,” Dr. Mitchell and Dr. McClain wrote.
Infection, kidney injury, and malnutrition are all significant concerns in patients with acute alcoholic hepatitis.
With respect to infection, the authors said considerable suspicion is required to pick up bacterial and fungal infections, as patients may not always have a fever and an elevated white blood cell count is an unreliable indicator. Infection also can lead to acute kidney injury.
Malnutrition is not only common in patients with alcohol hepatitis, but it has a significant negative impact on recovery. All patients should be encouraged to meet nutritional goals as early as possible, but just how to achieve this is controversial, the authors stressed.
For example, one study suggested that enteral nutrition was as good as glucocorticoids in reducing 28-day mortality, while another found enteral nutrition via nasogastric tube – in addition to glucocorticoids – was no better than glucocorticoids alone. “Whether [nasogastric] tubes should be used to provide enteral nutrition is a subject of controversy,” the authors wrote. “Normal- to high-protein diets are safe and do not increase the risk of encephalopathy in patients with AH.”
No conflicts of interest were declared.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Covered-stent TIPS tops large-volume paracentesis for cirrhosis survival
One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.
“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).
All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.
Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.
It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.
Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.
The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.
Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.
The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.
One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.
“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).
All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.
Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.
It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.
Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.
The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.
Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.
The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.
One-year survival without liver transplant was far more likely when transjugular intrahepatic portosystemic shunts (TIPS) with covered stents were used to treat cirrhosis with recurrent ascites, instead of ongoing large-volume paracenteses with albumin, in a 62-patient randomized trial from France.
“TIPS with covered stents ... should therefore be preferred to LVP [large-volume paracenteses] with volume expansion... These findings support TIPS as the first-line intervention,” said investigators led by gastroenterologist Christophe Bureau, MD, of Toulouse (France) University in the January issue of Gastroenterology (doi: 10.1053/j.gastro.2016.09.016).
All 62 patients had at least two LVPs prior to the study; 29 were then randomized to covered transjugular intrahepatic portosystemic shunt (TIPS), and 33 to LVP and albumin as needed. All the patients were on a low-salt diet.
Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003). TIPS patients had a total of 32 paracenteses in the first year, versus 320 in the LVP group. Six paracentesis patients (18%) had portal hypertension–related bleeding, and six had hernia-related complications; none of the TIPS patients had either. LVP patients spent a mean of 35 days in the hospital, versus 17 days for the TIPS group (P = .04). The probability of remaining free of encephalopathy at 1 year was the same in both groups, at 65%.
It has been shown before that TIPS has the edge on LVP for reducing recurrence of tense ascites. However, early studies used uncovered stents and, due to their almost 80% risk of dysfunction, they did not show a significant benefit for survival. As a result, repeated paracenteses have been recommended as first-line treatment, with TIPS held in reserve for patients who need very frequent LVP.
Polytetrafluoroethylene-covered stents appear to have changed the equation, “owing to a substantial decrease in the rate of shunt dysfunction,” the investigators said.
The French results are a bit better than previous reports of covered TIPS. “This could be related to greater experience with the TIPS procedure;” there were no technical failures. The study also mostly included patients younger than 65 years with Child-Pugh class B disease and no prior encephalopathy – favorable factors that also may have contributed to the results. However, “we believe that the use of covered stents was the main determinant of the observed improvement in outcomes... TIPS with uncovered stent[s] should not be considered effective or recommended any longer for the long-term treatment of” portal hypertension, they said.
Cirrhosis in the trial was due almost entirely to alcohol abuse. About three-quarters of both groups reported abstinence while enrolled. The mean age was 56 years, and the majority of subjects were men.
The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. Dr. Bureau and another author are Gore consultants.
FROM GASTROENTEROLOGY
Key clinical point:
Major finding: Twenty-seven TIPS patients (93%) were alive without a liver transplant at 1 year, versus 17 (52%) in the LVP group (P = .003).
Data source: Randomized trial with 62 patients.
Disclosures: The work was funded by the French Ministry of Health and supported by Gore, maker of the covered stent used in the study. The lead and one other investigator are Gore consultants.
Hepatitis Outlook: November 2016
If you work on the front lines of medical care treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, covering a variety of the major hepatitis viruses.
The introduction of universal mass vaccination against hepatitis A in countries with intermediate endemicity for HAV infection led to a considerable decrease in the incidence of HAV in vaccinated and in nonvaccinated age groups alike.
Mortality was high among chronic hepatitis C patients, with and without cirrhosis, compared with the general population, a Danish cohort study found. Curing CHC was associated with reduced mortality among cirrhotic patients but remained higher than the general population.
A hepatitis C outbreak in a North Dakota skilled nursing facility highlights the importance of prompt reporting and investigation of incident HCV infection, and the need for adherence to basic infection control procedures by health care personnel.
A recent study identified a novel hepatitis B virus subgenotype D10 circulating in Ethiopia, underlining the high genetic variability of HBV strains in Africa.
A study in the Journal of Viral Hepatitis found that baseline hepatitis B core antibody predicts treatment response in chronic hepatitis B patients receiving long-term entecavir.
A novel quantitative microarray antibody capture assay was able to identify extremely high hepatitis delta virus prevalence amongst hepatitis B virus–infected Mongolians.
The albumin-bilirubin (ALBI) score was effective in predicting the long-term prognosis for patients with hepatitis B virus–related cirrhosis and was more accurate than Child-Pugh and Model for End-Stage Liver Disease (MELD) scores.
A study in Hepatology found that proanthocyanidin (PAC) and its analogs present a new class of anti–hepatitis B virus agents that directly target the preS1 region of the HBV large surface protein and could contribute to the development of a potent, well-tolerated, and broadly active inhibitor of HBV infection.
A hepatitis C virus core antigen (HCV-Ag) assay proved to be useful in monitoring treatment of HCV-infected patients with sustained viral response and in patients who experienced treatment failures, according to a study in Diagnostic Microbiology and Infectious Disease.
The introduction of a managed care network for patients infected with hepatitis C virus increased access to care and reduced all-cause mortality, according to a recent study.
A study in South Korea found that hepatitis B infection was associated with an increased incidence of thrombocytopenia in healthy adults without cirrhosis.
A proof-of-concept study demonstrated that peritransplant immunoprophylaxis combined with a single oral direct-acting antiviral in the immediate post-transplant period can prevent HCV recurrence.
A study in the Journal of Viral Hepatitis established the baseline mortality and hepatocellular carcinoma progression rates in decompensated cirrhosis patients against which the impact of new antiviral therapies could be measured.
Genetic distance-based network analyses can be used to identify characteristics associated with hepatitis C virus transmission, informing targeted prevention and treatment strategies, according to a recent study.
According to a new study, primary T-cell immunodeficiency is associated with a lower spontaneous clearance of hepatitis C virus, while female sex and coinfection with hepatitis B virus are associated with a higher spontaneous clearance.
A study in the Journal of Viral Hepatitis found that the induction of humoral and cellular immune response to hepatitis B virus vaccine can be upregulated by CpG oligonucleotides complexed with Dectin-1 ligand.
[email protected]
On Twitter @richpizzi
If you work on the front lines of medical care treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, covering a variety of the major hepatitis viruses.
The introduction of universal mass vaccination against hepatitis A in countries with intermediate endemicity for HAV infection led to a considerable decrease in the incidence of HAV in vaccinated and in nonvaccinated age groups alike.
Mortality was high among chronic hepatitis C patients, with and without cirrhosis, compared with the general population, a Danish cohort study found. Curing CHC was associated with reduced mortality among cirrhotic patients but remained higher than the general population.
A hepatitis C outbreak in a North Dakota skilled nursing facility highlights the importance of prompt reporting and investigation of incident HCV infection, and the need for adherence to basic infection control procedures by health care personnel.
A recent study identified a novel hepatitis B virus subgenotype D10 circulating in Ethiopia, underlining the high genetic variability of HBV strains in Africa.
A study in the Journal of Viral Hepatitis found that baseline hepatitis B core antibody predicts treatment response in chronic hepatitis B patients receiving long-term entecavir.
A novel quantitative microarray antibody capture assay was able to identify extremely high hepatitis delta virus prevalence amongst hepatitis B virus–infected Mongolians.
The albumin-bilirubin (ALBI) score was effective in predicting the long-term prognosis for patients with hepatitis B virus–related cirrhosis and was more accurate than Child-Pugh and Model for End-Stage Liver Disease (MELD) scores.
A study in Hepatology found that proanthocyanidin (PAC) and its analogs present a new class of anti–hepatitis B virus agents that directly target the preS1 region of the HBV large surface protein and could contribute to the development of a potent, well-tolerated, and broadly active inhibitor of HBV infection.
A hepatitis C virus core antigen (HCV-Ag) assay proved to be useful in monitoring treatment of HCV-infected patients with sustained viral response and in patients who experienced treatment failures, according to a study in Diagnostic Microbiology and Infectious Disease.
The introduction of a managed care network for patients infected with hepatitis C virus increased access to care and reduced all-cause mortality, according to a recent study.
A study in South Korea found that hepatitis B infection was associated with an increased incidence of thrombocytopenia in healthy adults without cirrhosis.
A proof-of-concept study demonstrated that peritransplant immunoprophylaxis combined with a single oral direct-acting antiviral in the immediate post-transplant period can prevent HCV recurrence.
A study in the Journal of Viral Hepatitis established the baseline mortality and hepatocellular carcinoma progression rates in decompensated cirrhosis patients against which the impact of new antiviral therapies could be measured.
Genetic distance-based network analyses can be used to identify characteristics associated with hepatitis C virus transmission, informing targeted prevention and treatment strategies, according to a recent study.
According to a new study, primary T-cell immunodeficiency is associated with a lower spontaneous clearance of hepatitis C virus, while female sex and coinfection with hepatitis B virus are associated with a higher spontaneous clearance.
A study in the Journal of Viral Hepatitis found that the induction of humoral and cellular immune response to hepatitis B virus vaccine can be upregulated by CpG oligonucleotides complexed with Dectin-1 ligand.
[email protected]
On Twitter @richpizzi
If you work on the front lines of medical care treating patients with hepatitis, you may not have time to review all the hepatitis research that enters the medical literature every month. Here’s a quick look at some notable news items and journal articles published over the past month, covering a variety of the major hepatitis viruses.
The introduction of universal mass vaccination against hepatitis A in countries with intermediate endemicity for HAV infection led to a considerable decrease in the incidence of HAV in vaccinated and in nonvaccinated age groups alike.
Mortality was high among chronic hepatitis C patients, with and without cirrhosis, compared with the general population, a Danish cohort study found. Curing CHC was associated with reduced mortality among cirrhotic patients but remained higher than the general population.
A hepatitis C outbreak in a North Dakota skilled nursing facility highlights the importance of prompt reporting and investigation of incident HCV infection, and the need for adherence to basic infection control procedures by health care personnel.
A recent study identified a novel hepatitis B virus subgenotype D10 circulating in Ethiopia, underlining the high genetic variability of HBV strains in Africa.
A study in the Journal of Viral Hepatitis found that baseline hepatitis B core antibody predicts treatment response in chronic hepatitis B patients receiving long-term entecavir.
A novel quantitative microarray antibody capture assay was able to identify extremely high hepatitis delta virus prevalence amongst hepatitis B virus–infected Mongolians.
The albumin-bilirubin (ALBI) score was effective in predicting the long-term prognosis for patients with hepatitis B virus–related cirrhosis and was more accurate than Child-Pugh and Model for End-Stage Liver Disease (MELD) scores.
A study in Hepatology found that proanthocyanidin (PAC) and its analogs present a new class of anti–hepatitis B virus agents that directly target the preS1 region of the HBV large surface protein and could contribute to the development of a potent, well-tolerated, and broadly active inhibitor of HBV infection.
A hepatitis C virus core antigen (HCV-Ag) assay proved to be useful in monitoring treatment of HCV-infected patients with sustained viral response and in patients who experienced treatment failures, according to a study in Diagnostic Microbiology and Infectious Disease.
The introduction of a managed care network for patients infected with hepatitis C virus increased access to care and reduced all-cause mortality, according to a recent study.
A study in South Korea found that hepatitis B infection was associated with an increased incidence of thrombocytopenia in healthy adults without cirrhosis.
A proof-of-concept study demonstrated that peritransplant immunoprophylaxis combined with a single oral direct-acting antiviral in the immediate post-transplant period can prevent HCV recurrence.
A study in the Journal of Viral Hepatitis established the baseline mortality and hepatocellular carcinoma progression rates in decompensated cirrhosis patients against which the impact of new antiviral therapies could be measured.
Genetic distance-based network analyses can be used to identify characteristics associated with hepatitis C virus transmission, informing targeted prevention and treatment strategies, according to a recent study.
According to a new study, primary T-cell immunodeficiency is associated with a lower spontaneous clearance of hepatitis C virus, while female sex and coinfection with hepatitis B virus are associated with a higher spontaneous clearance.
A study in the Journal of Viral Hepatitis found that the induction of humoral and cellular immune response to hepatitis B virus vaccine can be upregulated by CpG oligonucleotides complexed with Dectin-1 ligand.
[email protected]
On Twitter @richpizzi
VIDEO: Angiogenesis has a role to play in NASH and NAFLD
BOSTON – A multimodal research process has provided clues to the role of angiogenesis in nonalcoholic fatty liver disease (NAFLD) and its more serious cousin, nonalcoholic steatohepatitis (NASH).
In constructing a protocol that began with patients, moved on to bioinformatics and then performed final validation in the petri dish, Savneet Kaur, PhD, and her colleagues were able to identify several angiogenesis genes likely to contribute to the development of NAFLD and NASH.
“We have seen angiogenic mechanisms and angiogenic genes in the pathophysiology of nonalcoholic fatty liver disease,” said Dr. Kaur, professor of biotechnology at Gautam Buddha Medical School, Greater Noida, India, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kaur said that she and her coinvestigators began with a small group of eight patients with NASH, and seven patients with NAFLD, and also with seven healthy control participants. Genetic analysis and comparison of these patients yielded differential expression of certain genes already known to be associated with angiogenesis in the NASH and NAFLD, but not the healthy control participants.
“We did a microarray analysis, a high throughput gene expression study, and then we selected around 25 to 26 genes which were associated with oxidative stress and angiogenesis,” said Dr. Kaur.
For validation of these genes, Dr. Kaur and her associates used a larger study group of about 150 participants, again approximately evenly divided between those with mild NAFLD, those with more severe steatohepatitis, and healthy controls. “We validated the angiogenic genes in the subject group, and found that around 13 genes are preferentially expressed.”
“About 13 genes including VEGFR1, PIK3CA, CXCL8, NOS3, EREG, CCL2, PRKCE, PPar-gamma, PROK2, RUNX1, SIRT1, HMOX1 and CXCR4 showed significantly different gene expression in the [reverse transcription–polymerase chain reaction] analysis in Gr3 as compared to Gr1 (P less than .05 for each), whereas genes such as PIK3CA, CXCL8, NOS3, CCL2, PROK2, RUNX1, and HMOX1 were differentially expressed in Gr3 in comparison to Gr2 (P less than .05 each). A few genes, PPar-gamma, SIRT1, VEGFR1, HMOX1, PIK3CA, CXCR4, PROK2, and CCL2, showed correlations with fibrosis scores, angiogenesis scores, and NAFLD activity scores of the patients,” wrote Dr. Kaur and her colleagues in the abstract accompanying the poster presentation.
Taking these candidate genes, Dr. Kaur and her colleagues conducted a bioinformatics analysis to determine which transcription factors were controlling the genes. “We wanted to study the pathway – the mechanisms – to determine the upregulation and downregulation of these genes,” said Dr. Kaur.
Finally, Dr. Kaur and her associates took an in vitro approach, using human steatotic hepatocytes and endothelial cells, since “angiogenesis is a property of endothelial cells.” The two types of cells were cultured together, and angiogenic function and gene expression were examined, and checked against the genes and pathways identified in the first two steps. They again saw expression of the angiogenic pathways in the cell culture model. This was consistent with what is seen in patients with NAFLD and NASH: “Definitely, there’s an increase in angiogenesis. There’s an increase in the endothelial cell proliferation, with more fat, more steatosis in the patients,” said Dr. Kaur. Some genes, said Dr. Kaur, are “really important” to this process. Her group is now investigating how the genes are regulated, in order to understand better the precise role of angiogenesis in steatohepatitis.
The study was part of a joint Indo-German project, and sponsored by the Indian Council for Medical Research and the German Federal Ministry of Education and Research. Dr. Kaur reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
BOSTON – A multimodal research process has provided clues to the role of angiogenesis in nonalcoholic fatty liver disease (NAFLD) and its more serious cousin, nonalcoholic steatohepatitis (NASH).
In constructing a protocol that began with patients, moved on to bioinformatics and then performed final validation in the petri dish, Savneet Kaur, PhD, and her colleagues were able to identify several angiogenesis genes likely to contribute to the development of NAFLD and NASH.
“We have seen angiogenic mechanisms and angiogenic genes in the pathophysiology of nonalcoholic fatty liver disease,” said Dr. Kaur, professor of biotechnology at Gautam Buddha Medical School, Greater Noida, India, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kaur said that she and her coinvestigators began with a small group of eight patients with NASH, and seven patients with NAFLD, and also with seven healthy control participants. Genetic analysis and comparison of these patients yielded differential expression of certain genes already known to be associated with angiogenesis in the NASH and NAFLD, but not the healthy control participants.
“We did a microarray analysis, a high throughput gene expression study, and then we selected around 25 to 26 genes which were associated with oxidative stress and angiogenesis,” said Dr. Kaur.
For validation of these genes, Dr. Kaur and her associates used a larger study group of about 150 participants, again approximately evenly divided between those with mild NAFLD, those with more severe steatohepatitis, and healthy controls. “We validated the angiogenic genes in the subject group, and found that around 13 genes are preferentially expressed.”
“About 13 genes including VEGFR1, PIK3CA, CXCL8, NOS3, EREG, CCL2, PRKCE, PPar-gamma, PROK2, RUNX1, SIRT1, HMOX1 and CXCR4 showed significantly different gene expression in the [reverse transcription–polymerase chain reaction] analysis in Gr3 as compared to Gr1 (P less than .05 for each), whereas genes such as PIK3CA, CXCL8, NOS3, CCL2, PROK2, RUNX1, and HMOX1 were differentially expressed in Gr3 in comparison to Gr2 (P less than .05 each). A few genes, PPar-gamma, SIRT1, VEGFR1, HMOX1, PIK3CA, CXCR4, PROK2, and CCL2, showed correlations with fibrosis scores, angiogenesis scores, and NAFLD activity scores of the patients,” wrote Dr. Kaur and her colleagues in the abstract accompanying the poster presentation.
Taking these candidate genes, Dr. Kaur and her colleagues conducted a bioinformatics analysis to determine which transcription factors were controlling the genes. “We wanted to study the pathway – the mechanisms – to determine the upregulation and downregulation of these genes,” said Dr. Kaur.
Finally, Dr. Kaur and her associates took an in vitro approach, using human steatotic hepatocytes and endothelial cells, since “angiogenesis is a property of endothelial cells.” The two types of cells were cultured together, and angiogenic function and gene expression were examined, and checked against the genes and pathways identified in the first two steps. They again saw expression of the angiogenic pathways in the cell culture model. This was consistent with what is seen in patients with NAFLD and NASH: “Definitely, there’s an increase in angiogenesis. There’s an increase in the endothelial cell proliferation, with more fat, more steatosis in the patients,” said Dr. Kaur. Some genes, said Dr. Kaur, are “really important” to this process. Her group is now investigating how the genes are regulated, in order to understand better the precise role of angiogenesis in steatohepatitis.
The study was part of a joint Indo-German project, and sponsored by the Indian Council for Medical Research and the German Federal Ministry of Education and Research. Dr. Kaur reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
BOSTON – A multimodal research process has provided clues to the role of angiogenesis in nonalcoholic fatty liver disease (NAFLD) and its more serious cousin, nonalcoholic steatohepatitis (NASH).
In constructing a protocol that began with patients, moved on to bioinformatics and then performed final validation in the petri dish, Savneet Kaur, PhD, and her colleagues were able to identify several angiogenesis genes likely to contribute to the development of NAFLD and NASH.
“We have seen angiogenic mechanisms and angiogenic genes in the pathophysiology of nonalcoholic fatty liver disease,” said Dr. Kaur, professor of biotechnology at Gautam Buddha Medical School, Greater Noida, India, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kaur said that she and her coinvestigators began with a small group of eight patients with NASH, and seven patients with NAFLD, and also with seven healthy control participants. Genetic analysis and comparison of these patients yielded differential expression of certain genes already known to be associated with angiogenesis in the NASH and NAFLD, but not the healthy control participants.
“We did a microarray analysis, a high throughput gene expression study, and then we selected around 25 to 26 genes which were associated with oxidative stress and angiogenesis,” said Dr. Kaur.
For validation of these genes, Dr. Kaur and her associates used a larger study group of about 150 participants, again approximately evenly divided between those with mild NAFLD, those with more severe steatohepatitis, and healthy controls. “We validated the angiogenic genes in the subject group, and found that around 13 genes are preferentially expressed.”
“About 13 genes including VEGFR1, PIK3CA, CXCL8, NOS3, EREG, CCL2, PRKCE, PPar-gamma, PROK2, RUNX1, SIRT1, HMOX1 and CXCR4 showed significantly different gene expression in the [reverse transcription–polymerase chain reaction] analysis in Gr3 as compared to Gr1 (P less than .05 for each), whereas genes such as PIK3CA, CXCL8, NOS3, CCL2, PROK2, RUNX1, and HMOX1 were differentially expressed in Gr3 in comparison to Gr2 (P less than .05 each). A few genes, PPar-gamma, SIRT1, VEGFR1, HMOX1, PIK3CA, CXCR4, PROK2, and CCL2, showed correlations with fibrosis scores, angiogenesis scores, and NAFLD activity scores of the patients,” wrote Dr. Kaur and her colleagues in the abstract accompanying the poster presentation.
Taking these candidate genes, Dr. Kaur and her colleagues conducted a bioinformatics analysis to determine which transcription factors were controlling the genes. “We wanted to study the pathway – the mechanisms – to determine the upregulation and downregulation of these genes,” said Dr. Kaur.
Finally, Dr. Kaur and her associates took an in vitro approach, using human steatotic hepatocytes and endothelial cells, since “angiogenesis is a property of endothelial cells.” The two types of cells were cultured together, and angiogenic function and gene expression were examined, and checked against the genes and pathways identified in the first two steps. They again saw expression of the angiogenic pathways in the cell culture model. This was consistent with what is seen in patients with NAFLD and NASH: “Definitely, there’s an increase in angiogenesis. There’s an increase in the endothelial cell proliferation, with more fat, more steatosis in the patients,” said Dr. Kaur. Some genes, said Dr. Kaur, are “really important” to this process. Her group is now investigating how the genes are regulated, in order to understand better the precise role of angiogenesis in steatohepatitis.
The study was part of a joint Indo-German project, and sponsored by the Indian Council for Medical Research and the German Federal Ministry of Education and Research. Dr. Kaur reported no relevant conflicts of interest.
[email protected]
On Twitter @karioakes
AT THE LIVER MEETING 2016
Key clinical point:
Major finding: PPar-gamma, SIRT1, VEGFR1, and other genes are associated with fibrosis, angiogenesis, and steatosis.
Data source: Human bioinformatics–in vitro exploration of genetic pathways associated with angiogenesis in NASH and nonalcoholic fatty liver disease (NAFLD).
Disclosures: The study was part of a joint Indo-German project, and funded by the Indian Council for Medical Research and the German Federal Ministry of Education and Research. Dr. Kaur reported no relevant financial disclosures.
