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Investigational HCV Regimens Ditch the Interferon
BOSTON – Poor interferon: It was once the favored (and virtually only) effective therapy for hepatitis C viral infections, and now clinicians can’t wait to get rid of it.
Several investigational interferon-free oral regimens were the focus of studies presented at the annual meeting of the American Association for the Study of Liver Diseases.
The regimens combine various flavors of direct-acting antivirals (DAAs), with or without interferon’s faithful sidekick ribavirin, in dizzying combinations with varying degrees of efficacy.
Triple Therapy With Only New Agents
A triple DAA regimen that has been under study consists of daclatasvir, an investigational viral NS5Areplication complex inhibitor; asunaprevir, an investigational NS3 protease inhibitor; and BMS-791325, a nonnucleoside NS5B polymerase inhibitor (all three were from Bristol-Myers Squibb). This cocktail yielded high sustained virologic response (SVR) rates after both 12 and 24 weeks of treatment in previously untreated noncirrhotic patients with hepatitis C virus (HCV) genotype 1 chronic infections.
"SVR4 [SVR at 4 weeks post therapy] was achieved in all treatment-naïve genotype patients with post-treatment data available, including harder-to-treat patients with genotype 1a infection, high viral load, non-cirrhotic IL28b genotype," said Dr. Gregory T. Everson, professor of medicine and director of the section of hepatology at the University of Colorado in Denver.
In pilot studies, a dual regimen of daclatasvir and asunaprevir for 24 weeks was effective in prior null responders with genotype 1b but not 1a infections, prompting the investigators to see whether a triple whammy could improve efficacy in genotype 1a infections, remain tolerable, and ideally, be effective when given for only 12 weeks.
The ongoing open-label study compares daclatasvir 60 mg daily, asunaprevir 200 mg twice daily, and BMS-791325 75 mg twice daily for 12 or 24 weeks; a second part of the study looking at the combination with a 150-mg-higher dose of the latter agent does not have mature data as yet.
In a modified intention-to-treat analysis at 4 weeks of treatment, all 16 patients in a 24-week treatment cohort had HCV RNA levels below the lower limit of quantification (LLOQ). A the primary end point of 12 weeks, 15 (94%) had maintained viral suppression. At week 4 post treatment, 15 of the 16 patients still had viral RNA below the quantifiable level, for an SVR4 rate of 94%. One patient in this cohort withdrew from the trial at week 9 and is therefore considered a treatment failure.
In a second cohort of 16 patients treated for 12 weeks, rates of below-target or undetectable HCV RNA were 100% at treatment week 4, and 88% at week 12. Two patients who had withdrawn from the trial before the protocol-defined last treatment and therefore were not included in the 12-week analysis also had RNA levels below the LLOQ on subsequent visits, Dr. Everson said. The SVR4 and SVR12 rates were each 94% in this cohort.
The regimen was generally tolerated. No patients dropped out of the study due to adverse drug-related events, and no cases of viral breakthrough or post-treatment relapse have been reported to date, Dr. Everson said.
Ribavirin Optional
In another study, Dr. Mark S. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore, and his colleagues reported on a combination of daclatasvir and Gilead’s HCV polymerase inhibitor sofosbuvir with or without ribavirin, in patients with HCV genotypes 1, 2, and 3.
They looked at the combination of the two DAAs with or without ribavirin for 24 weeks of treatment in treatment-naïve patients with genotypes 1a or 1b, 2, and 3, and in two separate arms for 12 weeks in patients infected with genotypes 1a or 1b.
In the open-label trial, patients were randomly assigned to one of eight treatment groups. A total of 44 patients infected with genotypes 2 or 3 were assigned to receive daclatasvir 60 mg and sofosbuvir 400 mg daily, with one group also receiving ribavirin. In addition, 44 patients with genotypes 1a or 1b were assigned to daclatasvir and sofosbuvir at the same doses, with or without ribavirin, and in a separate randomization, 82 patients with genotype 1a or 1b were assigned to receive 12 weeks of the two DAAs with or without ribavirin.
The authors found that the combinations achieved SVRs in more than 93% of the entire patient sample. Among 44 patients with genotypes 2 or 3, 93% had an SVR24 rate of 93%, with 1 patient having a confirmed relapse.
Among 126 patients with genotype 1, 96% of those who had reached 12 weeks post treatment had an SVR12, including 3 who did not have an SVR4. The SVR24 rate in this group was 98%. One patient in this group was reinfected with a new HCV strain.
"Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin," Dr. Sulkowski said.
He noted that the combination was generally well tolerated, with low hemoglobin – often a concern with DAAs – occurring only among those patients who received ribavirin.
Sofosbuvir Stands Alone (Almost)
Another relatively simple regimen that was well tolerated and achieved sustained virologic response in some patients was a combination of sofosbuvir and weight-based or low-dose ribavirin. This combination was associated with a significant number of relapses, however.
Dr. Anu Osinusi, a clinical investigator at the National Institute of Allergy and Infectious Diseases, sought to determine whether a less complex and more tolerable regimen could be effective in an urban population with untreated HCV infection.
They enrolled 60 patients with HCV genotype 1. The majority of the patients were African Americans. In part 1 of the trial, the patients had stage 0 to 2 fibrosis. Part 2 of the trial included patients with all stages, including those with Child-Pugh Class A disease. Patients in part 1 received sofosbuvir 400 mg plus ribavirin 1,000-1,200 mg (10 patients). In part 2, 25 patients each were randomized either to the regimen above or to the same dose of sofosbuvir with low-dose ribavirin (600 mg).
In an interim intention-to-treat analysis, there was one dropout in part 1, and the remaining nine patients all had HCV RNA less than the LLOQ at weeks 4 and 12, at end of treatment, and maintained them out to SVR12.
In the second, randomized phase, 1 patient dropped out at week 3 of treatment in the full-dose ribavirin group; the remaining 24 patients all had RNA undetectable or below target at weeks 4, 12, and end of treatment, but by post-treatment week 4, 6 patients had relapse, yielding an SVR4 of 72%.
In the low-dose ribavirin arm, 3 patients dropped out by week 8. The remaining 22 patients, while on treatment, all had viral suppression at week 4, but 4 weeks after the end of therapy, 8 patients had relapsed, leaving an SVR4 of 56% (64% in a modified intention-to-treat analysis). "Ongoing analysis is currently focused on identifying the biologic correlates of HCV clearance, as well as identifying the mechanisms of relapse," Dr. Osinusi said.
The relapses were independent of baseline factors such as HCV RNA level, IL28B genotype, weight, race, degree of fibrosis, and ribavirin dose.
Both regimens were well tolerated, and both produced significant improvement of inflammation with treatment.
Dr. Everson’s study was supported by Bristol-Myers Squibb. He has received research support from the company. Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Osinusi’s study was funded by the National Institutes of Health. She reported having no relevant financial disclosures.
BOSTON – Poor interferon: It was once the favored (and virtually only) effective therapy for hepatitis C viral infections, and now clinicians can’t wait to get rid of it.
Several investigational interferon-free oral regimens were the focus of studies presented at the annual meeting of the American Association for the Study of Liver Diseases.
The regimens combine various flavors of direct-acting antivirals (DAAs), with or without interferon’s faithful sidekick ribavirin, in dizzying combinations with varying degrees of efficacy.
Triple Therapy With Only New Agents
A triple DAA regimen that has been under study consists of daclatasvir, an investigational viral NS5Areplication complex inhibitor; asunaprevir, an investigational NS3 protease inhibitor; and BMS-791325, a nonnucleoside NS5B polymerase inhibitor (all three were from Bristol-Myers Squibb). This cocktail yielded high sustained virologic response (SVR) rates after both 12 and 24 weeks of treatment in previously untreated noncirrhotic patients with hepatitis C virus (HCV) genotype 1 chronic infections.
"SVR4 [SVR at 4 weeks post therapy] was achieved in all treatment-naïve genotype patients with post-treatment data available, including harder-to-treat patients with genotype 1a infection, high viral load, non-cirrhotic IL28b genotype," said Dr. Gregory T. Everson, professor of medicine and director of the section of hepatology at the University of Colorado in Denver.
In pilot studies, a dual regimen of daclatasvir and asunaprevir for 24 weeks was effective in prior null responders with genotype 1b but not 1a infections, prompting the investigators to see whether a triple whammy could improve efficacy in genotype 1a infections, remain tolerable, and ideally, be effective when given for only 12 weeks.
The ongoing open-label study compares daclatasvir 60 mg daily, asunaprevir 200 mg twice daily, and BMS-791325 75 mg twice daily for 12 or 24 weeks; a second part of the study looking at the combination with a 150-mg-higher dose of the latter agent does not have mature data as yet.
In a modified intention-to-treat analysis at 4 weeks of treatment, all 16 patients in a 24-week treatment cohort had HCV RNA levels below the lower limit of quantification (LLOQ). A the primary end point of 12 weeks, 15 (94%) had maintained viral suppression. At week 4 post treatment, 15 of the 16 patients still had viral RNA below the quantifiable level, for an SVR4 rate of 94%. One patient in this cohort withdrew from the trial at week 9 and is therefore considered a treatment failure.
In a second cohort of 16 patients treated for 12 weeks, rates of below-target or undetectable HCV RNA were 100% at treatment week 4, and 88% at week 12. Two patients who had withdrawn from the trial before the protocol-defined last treatment and therefore were not included in the 12-week analysis also had RNA levels below the LLOQ on subsequent visits, Dr. Everson said. The SVR4 and SVR12 rates were each 94% in this cohort.
The regimen was generally tolerated. No patients dropped out of the study due to adverse drug-related events, and no cases of viral breakthrough or post-treatment relapse have been reported to date, Dr. Everson said.
Ribavirin Optional
In another study, Dr. Mark S. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore, and his colleagues reported on a combination of daclatasvir and Gilead’s HCV polymerase inhibitor sofosbuvir with or without ribavirin, in patients with HCV genotypes 1, 2, and 3.
They looked at the combination of the two DAAs with or without ribavirin for 24 weeks of treatment in treatment-naïve patients with genotypes 1a or 1b, 2, and 3, and in two separate arms for 12 weeks in patients infected with genotypes 1a or 1b.
In the open-label trial, patients were randomly assigned to one of eight treatment groups. A total of 44 patients infected with genotypes 2 or 3 were assigned to receive daclatasvir 60 mg and sofosbuvir 400 mg daily, with one group also receiving ribavirin. In addition, 44 patients with genotypes 1a or 1b were assigned to daclatasvir and sofosbuvir at the same doses, with or without ribavirin, and in a separate randomization, 82 patients with genotype 1a or 1b were assigned to receive 12 weeks of the two DAAs with or without ribavirin.
The authors found that the combinations achieved SVRs in more than 93% of the entire patient sample. Among 44 patients with genotypes 2 or 3, 93% had an SVR24 rate of 93%, with 1 patient having a confirmed relapse.
Among 126 patients with genotype 1, 96% of those who had reached 12 weeks post treatment had an SVR12, including 3 who did not have an SVR4. The SVR24 rate in this group was 98%. One patient in this group was reinfected with a new HCV strain.
"Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin," Dr. Sulkowski said.
He noted that the combination was generally well tolerated, with low hemoglobin – often a concern with DAAs – occurring only among those patients who received ribavirin.
Sofosbuvir Stands Alone (Almost)
Another relatively simple regimen that was well tolerated and achieved sustained virologic response in some patients was a combination of sofosbuvir and weight-based or low-dose ribavirin. This combination was associated with a significant number of relapses, however.
Dr. Anu Osinusi, a clinical investigator at the National Institute of Allergy and Infectious Diseases, sought to determine whether a less complex and more tolerable regimen could be effective in an urban population with untreated HCV infection.
They enrolled 60 patients with HCV genotype 1. The majority of the patients were African Americans. In part 1 of the trial, the patients had stage 0 to 2 fibrosis. Part 2 of the trial included patients with all stages, including those with Child-Pugh Class A disease. Patients in part 1 received sofosbuvir 400 mg plus ribavirin 1,000-1,200 mg (10 patients). In part 2, 25 patients each were randomized either to the regimen above or to the same dose of sofosbuvir with low-dose ribavirin (600 mg).
In an interim intention-to-treat analysis, there was one dropout in part 1, and the remaining nine patients all had HCV RNA less than the LLOQ at weeks 4 and 12, at end of treatment, and maintained them out to SVR12.
In the second, randomized phase, 1 patient dropped out at week 3 of treatment in the full-dose ribavirin group; the remaining 24 patients all had RNA undetectable or below target at weeks 4, 12, and end of treatment, but by post-treatment week 4, 6 patients had relapse, yielding an SVR4 of 72%.
In the low-dose ribavirin arm, 3 patients dropped out by week 8. The remaining 22 patients, while on treatment, all had viral suppression at week 4, but 4 weeks after the end of therapy, 8 patients had relapsed, leaving an SVR4 of 56% (64% in a modified intention-to-treat analysis). "Ongoing analysis is currently focused on identifying the biologic correlates of HCV clearance, as well as identifying the mechanisms of relapse," Dr. Osinusi said.
The relapses were independent of baseline factors such as HCV RNA level, IL28B genotype, weight, race, degree of fibrosis, and ribavirin dose.
Both regimens were well tolerated, and both produced significant improvement of inflammation with treatment.
Dr. Everson’s study was supported by Bristol-Myers Squibb. He has received research support from the company. Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Osinusi’s study was funded by the National Institutes of Health. She reported having no relevant financial disclosures.
BOSTON – Poor interferon: It was once the favored (and virtually only) effective therapy for hepatitis C viral infections, and now clinicians can’t wait to get rid of it.
Several investigational interferon-free oral regimens were the focus of studies presented at the annual meeting of the American Association for the Study of Liver Diseases.
The regimens combine various flavors of direct-acting antivirals (DAAs), with or without interferon’s faithful sidekick ribavirin, in dizzying combinations with varying degrees of efficacy.
Triple Therapy With Only New Agents
A triple DAA regimen that has been under study consists of daclatasvir, an investigational viral NS5Areplication complex inhibitor; asunaprevir, an investigational NS3 protease inhibitor; and BMS-791325, a nonnucleoside NS5B polymerase inhibitor (all three were from Bristol-Myers Squibb). This cocktail yielded high sustained virologic response (SVR) rates after both 12 and 24 weeks of treatment in previously untreated noncirrhotic patients with hepatitis C virus (HCV) genotype 1 chronic infections.
"SVR4 [SVR at 4 weeks post therapy] was achieved in all treatment-naïve genotype patients with post-treatment data available, including harder-to-treat patients with genotype 1a infection, high viral load, non-cirrhotic IL28b genotype," said Dr. Gregory T. Everson, professor of medicine and director of the section of hepatology at the University of Colorado in Denver.
In pilot studies, a dual regimen of daclatasvir and asunaprevir for 24 weeks was effective in prior null responders with genotype 1b but not 1a infections, prompting the investigators to see whether a triple whammy could improve efficacy in genotype 1a infections, remain tolerable, and ideally, be effective when given for only 12 weeks.
The ongoing open-label study compares daclatasvir 60 mg daily, asunaprevir 200 mg twice daily, and BMS-791325 75 mg twice daily for 12 or 24 weeks; a second part of the study looking at the combination with a 150-mg-higher dose of the latter agent does not have mature data as yet.
In a modified intention-to-treat analysis at 4 weeks of treatment, all 16 patients in a 24-week treatment cohort had HCV RNA levels below the lower limit of quantification (LLOQ). A the primary end point of 12 weeks, 15 (94%) had maintained viral suppression. At week 4 post treatment, 15 of the 16 patients still had viral RNA below the quantifiable level, for an SVR4 rate of 94%. One patient in this cohort withdrew from the trial at week 9 and is therefore considered a treatment failure.
In a second cohort of 16 patients treated for 12 weeks, rates of below-target or undetectable HCV RNA were 100% at treatment week 4, and 88% at week 12. Two patients who had withdrawn from the trial before the protocol-defined last treatment and therefore were not included in the 12-week analysis also had RNA levels below the LLOQ on subsequent visits, Dr. Everson said. The SVR4 and SVR12 rates were each 94% in this cohort.
The regimen was generally tolerated. No patients dropped out of the study due to adverse drug-related events, and no cases of viral breakthrough or post-treatment relapse have been reported to date, Dr. Everson said.
Ribavirin Optional
In another study, Dr. Mark S. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore, and his colleagues reported on a combination of daclatasvir and Gilead’s HCV polymerase inhibitor sofosbuvir with or without ribavirin, in patients with HCV genotypes 1, 2, and 3.
They looked at the combination of the two DAAs with or without ribavirin for 24 weeks of treatment in treatment-naïve patients with genotypes 1a or 1b, 2, and 3, and in two separate arms for 12 weeks in patients infected with genotypes 1a or 1b.
In the open-label trial, patients were randomly assigned to one of eight treatment groups. A total of 44 patients infected with genotypes 2 or 3 were assigned to receive daclatasvir 60 mg and sofosbuvir 400 mg daily, with one group also receiving ribavirin. In addition, 44 patients with genotypes 1a or 1b were assigned to daclatasvir and sofosbuvir at the same doses, with or without ribavirin, and in a separate randomization, 82 patients with genotype 1a or 1b were assigned to receive 12 weeks of the two DAAs with or without ribavirin.
The authors found that the combinations achieved SVRs in more than 93% of the entire patient sample. Among 44 patients with genotypes 2 or 3, 93% had an SVR24 rate of 93%, with 1 patient having a confirmed relapse.
Among 126 patients with genotype 1, 96% of those who had reached 12 weeks post treatment had an SVR12, including 3 who did not have an SVR4. The SVR24 rate in this group was 98%. One patient in this group was reinfected with a new HCV strain.
"Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin," Dr. Sulkowski said.
He noted that the combination was generally well tolerated, with low hemoglobin – often a concern with DAAs – occurring only among those patients who received ribavirin.
Sofosbuvir Stands Alone (Almost)
Another relatively simple regimen that was well tolerated and achieved sustained virologic response in some patients was a combination of sofosbuvir and weight-based or low-dose ribavirin. This combination was associated with a significant number of relapses, however.
Dr. Anu Osinusi, a clinical investigator at the National Institute of Allergy and Infectious Diseases, sought to determine whether a less complex and more tolerable regimen could be effective in an urban population with untreated HCV infection.
They enrolled 60 patients with HCV genotype 1. The majority of the patients were African Americans. In part 1 of the trial, the patients had stage 0 to 2 fibrosis. Part 2 of the trial included patients with all stages, including those with Child-Pugh Class A disease. Patients in part 1 received sofosbuvir 400 mg plus ribavirin 1,000-1,200 mg (10 patients). In part 2, 25 patients each were randomized either to the regimen above or to the same dose of sofosbuvir with low-dose ribavirin (600 mg).
In an interim intention-to-treat analysis, there was one dropout in part 1, and the remaining nine patients all had HCV RNA less than the LLOQ at weeks 4 and 12, at end of treatment, and maintained them out to SVR12.
In the second, randomized phase, 1 patient dropped out at week 3 of treatment in the full-dose ribavirin group; the remaining 24 patients all had RNA undetectable or below target at weeks 4, 12, and end of treatment, but by post-treatment week 4, 6 patients had relapse, yielding an SVR4 of 72%.
In the low-dose ribavirin arm, 3 patients dropped out by week 8. The remaining 22 patients, while on treatment, all had viral suppression at week 4, but 4 weeks after the end of therapy, 8 patients had relapsed, leaving an SVR4 of 56% (64% in a modified intention-to-treat analysis). "Ongoing analysis is currently focused on identifying the biologic correlates of HCV clearance, as well as identifying the mechanisms of relapse," Dr. Osinusi said.
The relapses were independent of baseline factors such as HCV RNA level, IL28B genotype, weight, race, degree of fibrosis, and ribavirin dose.
Both regimens were well tolerated, and both produced significant improvement of inflammation with treatment.
Dr. Everson’s study was supported by Bristol-Myers Squibb. He has received research support from the company. Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Osinusi’s study was funded by the National Institutes of Health. She reported having no relevant financial disclosures.
AT THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
Kidneys Benefited From Everolimus After Liver Transplant
BOSTON – Everolimus given with a reduced dose of tacrolimus to liver transplant patients yielded similar rates of acute rejection, graft loss, and death, but better kidney function than standard-dose tacrolimus alone at 2 years in a randomized, open-label, multicenter, controlled trial.
These 2-year results confirm and build on the recently published results of the trial at 1 year (Am. J. Transpl. 2012;12:3008-20), lead investigator Dr. Faouzi Saliba of Paul Brousse Hospital, Villejuif, France, reported at the annual meeting of the American Association for the Study of Liver Diseases.
Since the first study was published 9 years ago documenting a cumulative incidence of chronic renal failure of 28% after 10 years of tacrolimus treatment after liver transplant (N. Engl. J. Med. 2003;349:931-40), another study has reported estimated glomerular filtration rates (eGFRs) of less than 60 mL/min per 1.73 m2 (stage 3 chronic kidney failure) for 58% of liver transplant recipients after 5 years of treatment with tacrolimus (Liver Transpl. 2009:15:1083-91).
On the basis of the effectiveness of everolimus in reducing the dose of calcineurin inhibitor needed for immunosuppression without reducing efficacy in patients with de novo kidney transplantation (Am. J. Transpl. 2010;10:1401-13), Dr. Saliba and his coinvestigators conducted the current trial.
Following a 30-day run-in period in which liver transplant recipients received tacrolimus with or without mycophenolate mofetil and prednisone, the investigators randomized 719 patients to three arms: two arms with everolimus 3-8 ng/mL, tacrolimus reduced to 3-5 ng/mL, and prednisone, and a control arm with tacrolimus dosed to a standard 8-12 ng/mL plus prednisone. After 4 months, in one of the reduced-dose arms, tacrolimus was withdrawn and the everolimus dose was increased to 8-10 ng/mL (231 patients), whereas the dose of everolimus was kept constant in the other reduced-dose arm (245 patients) and the dose of tacrolimus was kept the same in the control arm (243 patients). Prednisone could be eliminated at 4 months in any arm. However, enrollment into the tacrolimus withdrawal arm was stopped at the time of conversion to everolimus alone because of a high rate of rejection episodes, and the trial’s protocol was amended to compare efficacy between only the reduced-dose and control arms.
By 2 years, the number of patients who completed the study was similar in both the reduced-dose and control arms (82% vs. 84%, respectively), and similar percentages in each group remained on the study medications at 2 years (58% vs. 68%, respectively).
In each group, recipients were mostly men (74%) and white (80%-86%), with a mean age of 54 years and mean donor age of 49 years. They had a Model for End-Stage Liver Disease score of 19, and eGFRs of about 80 mL/min per 1.73 m2.
Mean levels of tacrolimus dropped from 10.5 ng/mL at randomization to 4 ng/mL at 2 years in the dose-reduction arm, compared with 10 ng/mL to 7 ng/mL in the control arm.
At 2 years in the intent-to-treat population, the groups had similar rates of the composite primary end point of treated biopsy-proven acute rejection, graft failure, and death (10.5% in the dose-reduction arm and 12.5% in the control arm). Biopsy-proven acute rejection occurred at a significantly lower rate among dose-reduced patients (6%) than among control patients (13%). All of the episodes of acute rejection in the tacrolimus dose-reduced patients were borderline or mild based on the Banff rejection activity index. However, liver biopsies at 1 and 2 years were only part of the trial’s protocol for hepatitis C virus (HCV)-infected patients. The decision to biopsy was otherwise left up to the physicians of each center.
At 1 year, there appeared to be less fibrosis in patients who received everolimus, Dr. Saliba said in response to a question from the audience. In about half of the 75 HCV-infected patients in the dose-reduction arm, liver biopsies showed less fibrosis of at least stage 1 than in patients with HCV infection in the other group. The investigators are now analyzing 2-year data, he said.
The dose-reduced group maintained significantly better eGFR than the control group, through the duration of the trial, finishing with levels of 66 vs. 78 mL/min per 1.73 m2.
Several types of adverse events with an incidence of at least 10% occurred more often in the dose-reduction arm than in the control arm, including leucopenia (13% vs. 5%), peripheral edema (20% vs. 13%), and hypercholesterolemia (11% vs. 4%).
Proteinuria of less than 0.5 g/24 hours occurred in 92%-93% of the patients; none of the patients had severe proteinuria of 3 g/24 hours or more.
One audience member noted that the most important patients to study in this clinical population are those on the borderline of renal failure with low eGFR and elevated creatinine, who would benefit most from improved renal function. Dr. Saliba said that at the time of randomization, the investigators looked at levels of eGFR in each group and over the course of the 2 years, more patients in the standard-dose tacrolimus arm had worsened renal function, whereas many in the dose-reduction arm had improved or at least stable renal function, and few had worsened function.
The study was sponsored by Novartis, which manufactures everolimus. Dr. Saliba reported financial ties to Novartis and Astellas Pharma (manufacturer of tacrolimus), as well as other companies that manufacture drugs used by liver transplant patients. Several other investigators reported financial ties to companies that manufacture antirejection drugs used in liver transplant patients, including Novartis. Three study investigators are employees of Novartis.
BOSTON – Everolimus given with a reduced dose of tacrolimus to liver transplant patients yielded similar rates of acute rejection, graft loss, and death, but better kidney function than standard-dose tacrolimus alone at 2 years in a randomized, open-label, multicenter, controlled trial.
These 2-year results confirm and build on the recently published results of the trial at 1 year (Am. J. Transpl. 2012;12:3008-20), lead investigator Dr. Faouzi Saliba of Paul Brousse Hospital, Villejuif, France, reported at the annual meeting of the American Association for the Study of Liver Diseases.
Since the first study was published 9 years ago documenting a cumulative incidence of chronic renal failure of 28% after 10 years of tacrolimus treatment after liver transplant (N. Engl. J. Med. 2003;349:931-40), another study has reported estimated glomerular filtration rates (eGFRs) of less than 60 mL/min per 1.73 m2 (stage 3 chronic kidney failure) for 58% of liver transplant recipients after 5 years of treatment with tacrolimus (Liver Transpl. 2009:15:1083-91).
On the basis of the effectiveness of everolimus in reducing the dose of calcineurin inhibitor needed for immunosuppression without reducing efficacy in patients with de novo kidney transplantation (Am. J. Transpl. 2010;10:1401-13), Dr. Saliba and his coinvestigators conducted the current trial.
Following a 30-day run-in period in which liver transplant recipients received tacrolimus with or without mycophenolate mofetil and prednisone, the investigators randomized 719 patients to three arms: two arms with everolimus 3-8 ng/mL, tacrolimus reduced to 3-5 ng/mL, and prednisone, and a control arm with tacrolimus dosed to a standard 8-12 ng/mL plus prednisone. After 4 months, in one of the reduced-dose arms, tacrolimus was withdrawn and the everolimus dose was increased to 8-10 ng/mL (231 patients), whereas the dose of everolimus was kept constant in the other reduced-dose arm (245 patients) and the dose of tacrolimus was kept the same in the control arm (243 patients). Prednisone could be eliminated at 4 months in any arm. However, enrollment into the tacrolimus withdrawal arm was stopped at the time of conversion to everolimus alone because of a high rate of rejection episodes, and the trial’s protocol was amended to compare efficacy between only the reduced-dose and control arms.
By 2 years, the number of patients who completed the study was similar in both the reduced-dose and control arms (82% vs. 84%, respectively), and similar percentages in each group remained on the study medications at 2 years (58% vs. 68%, respectively).
In each group, recipients were mostly men (74%) and white (80%-86%), with a mean age of 54 years and mean donor age of 49 years. They had a Model for End-Stage Liver Disease score of 19, and eGFRs of about 80 mL/min per 1.73 m2.
Mean levels of tacrolimus dropped from 10.5 ng/mL at randomization to 4 ng/mL at 2 years in the dose-reduction arm, compared with 10 ng/mL to 7 ng/mL in the control arm.
At 2 years in the intent-to-treat population, the groups had similar rates of the composite primary end point of treated biopsy-proven acute rejection, graft failure, and death (10.5% in the dose-reduction arm and 12.5% in the control arm). Biopsy-proven acute rejection occurred at a significantly lower rate among dose-reduced patients (6%) than among control patients (13%). All of the episodes of acute rejection in the tacrolimus dose-reduced patients were borderline or mild based on the Banff rejection activity index. However, liver biopsies at 1 and 2 years were only part of the trial’s protocol for hepatitis C virus (HCV)-infected patients. The decision to biopsy was otherwise left up to the physicians of each center.
At 1 year, there appeared to be less fibrosis in patients who received everolimus, Dr. Saliba said in response to a question from the audience. In about half of the 75 HCV-infected patients in the dose-reduction arm, liver biopsies showed less fibrosis of at least stage 1 than in patients with HCV infection in the other group. The investigators are now analyzing 2-year data, he said.
The dose-reduced group maintained significantly better eGFR than the control group, through the duration of the trial, finishing with levels of 66 vs. 78 mL/min per 1.73 m2.
Several types of adverse events with an incidence of at least 10% occurred more often in the dose-reduction arm than in the control arm, including leucopenia (13% vs. 5%), peripheral edema (20% vs. 13%), and hypercholesterolemia (11% vs. 4%).
Proteinuria of less than 0.5 g/24 hours occurred in 92%-93% of the patients; none of the patients had severe proteinuria of 3 g/24 hours or more.
One audience member noted that the most important patients to study in this clinical population are those on the borderline of renal failure with low eGFR and elevated creatinine, who would benefit most from improved renal function. Dr. Saliba said that at the time of randomization, the investigators looked at levels of eGFR in each group and over the course of the 2 years, more patients in the standard-dose tacrolimus arm had worsened renal function, whereas many in the dose-reduction arm had improved or at least stable renal function, and few had worsened function.
The study was sponsored by Novartis, which manufactures everolimus. Dr. Saliba reported financial ties to Novartis and Astellas Pharma (manufacturer of tacrolimus), as well as other companies that manufacture drugs used by liver transplant patients. Several other investigators reported financial ties to companies that manufacture antirejection drugs used in liver transplant patients, including Novartis. Three study investigators are employees of Novartis.
BOSTON – Everolimus given with a reduced dose of tacrolimus to liver transplant patients yielded similar rates of acute rejection, graft loss, and death, but better kidney function than standard-dose tacrolimus alone at 2 years in a randomized, open-label, multicenter, controlled trial.
These 2-year results confirm and build on the recently published results of the trial at 1 year (Am. J. Transpl. 2012;12:3008-20), lead investigator Dr. Faouzi Saliba of Paul Brousse Hospital, Villejuif, France, reported at the annual meeting of the American Association for the Study of Liver Diseases.
Since the first study was published 9 years ago documenting a cumulative incidence of chronic renal failure of 28% after 10 years of tacrolimus treatment after liver transplant (N. Engl. J. Med. 2003;349:931-40), another study has reported estimated glomerular filtration rates (eGFRs) of less than 60 mL/min per 1.73 m2 (stage 3 chronic kidney failure) for 58% of liver transplant recipients after 5 years of treatment with tacrolimus (Liver Transpl. 2009:15:1083-91).
On the basis of the effectiveness of everolimus in reducing the dose of calcineurin inhibitor needed for immunosuppression without reducing efficacy in patients with de novo kidney transplantation (Am. J. Transpl. 2010;10:1401-13), Dr. Saliba and his coinvestigators conducted the current trial.
Following a 30-day run-in period in which liver transplant recipients received tacrolimus with or without mycophenolate mofetil and prednisone, the investigators randomized 719 patients to three arms: two arms with everolimus 3-8 ng/mL, tacrolimus reduced to 3-5 ng/mL, and prednisone, and a control arm with tacrolimus dosed to a standard 8-12 ng/mL plus prednisone. After 4 months, in one of the reduced-dose arms, tacrolimus was withdrawn and the everolimus dose was increased to 8-10 ng/mL (231 patients), whereas the dose of everolimus was kept constant in the other reduced-dose arm (245 patients) and the dose of tacrolimus was kept the same in the control arm (243 patients). Prednisone could be eliminated at 4 months in any arm. However, enrollment into the tacrolimus withdrawal arm was stopped at the time of conversion to everolimus alone because of a high rate of rejection episodes, and the trial’s protocol was amended to compare efficacy between only the reduced-dose and control arms.
By 2 years, the number of patients who completed the study was similar in both the reduced-dose and control arms (82% vs. 84%, respectively), and similar percentages in each group remained on the study medications at 2 years (58% vs. 68%, respectively).
In each group, recipients were mostly men (74%) and white (80%-86%), with a mean age of 54 years and mean donor age of 49 years. They had a Model for End-Stage Liver Disease score of 19, and eGFRs of about 80 mL/min per 1.73 m2.
Mean levels of tacrolimus dropped from 10.5 ng/mL at randomization to 4 ng/mL at 2 years in the dose-reduction arm, compared with 10 ng/mL to 7 ng/mL in the control arm.
At 2 years in the intent-to-treat population, the groups had similar rates of the composite primary end point of treated biopsy-proven acute rejection, graft failure, and death (10.5% in the dose-reduction arm and 12.5% in the control arm). Biopsy-proven acute rejection occurred at a significantly lower rate among dose-reduced patients (6%) than among control patients (13%). All of the episodes of acute rejection in the tacrolimus dose-reduced patients were borderline or mild based on the Banff rejection activity index. However, liver biopsies at 1 and 2 years were only part of the trial’s protocol for hepatitis C virus (HCV)-infected patients. The decision to biopsy was otherwise left up to the physicians of each center.
At 1 year, there appeared to be less fibrosis in patients who received everolimus, Dr. Saliba said in response to a question from the audience. In about half of the 75 HCV-infected patients in the dose-reduction arm, liver biopsies showed less fibrosis of at least stage 1 than in patients with HCV infection in the other group. The investigators are now analyzing 2-year data, he said.
The dose-reduced group maintained significantly better eGFR than the control group, through the duration of the trial, finishing with levels of 66 vs. 78 mL/min per 1.73 m2.
Several types of adverse events with an incidence of at least 10% occurred more often in the dose-reduction arm than in the control arm, including leucopenia (13% vs. 5%), peripheral edema (20% vs. 13%), and hypercholesterolemia (11% vs. 4%).
Proteinuria of less than 0.5 g/24 hours occurred in 92%-93% of the patients; none of the patients had severe proteinuria of 3 g/24 hours or more.
One audience member noted that the most important patients to study in this clinical population are those on the borderline of renal failure with low eGFR and elevated creatinine, who would benefit most from improved renal function. Dr. Saliba said that at the time of randomization, the investigators looked at levels of eGFR in each group and over the course of the 2 years, more patients in the standard-dose tacrolimus arm had worsened renal function, whereas many in the dose-reduction arm had improved or at least stable renal function, and few had worsened function.
The study was sponsored by Novartis, which manufactures everolimus. Dr. Saliba reported financial ties to Novartis and Astellas Pharma (manufacturer of tacrolimus), as well as other companies that manufacture drugs used by liver transplant patients. Several other investigators reported financial ties to companies that manufacture antirejection drugs used in liver transplant patients, including Novartis. Three study investigators are employees of Novartis.
AT THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
Major Finding: At 2 years in the intent-to-treat population, the groups had similar rates of the composite primary end point of treated biopsy-proven acute rejection, graft failure, and death (10.5% in the dose-reduction arm and 12.5% in the control arm).
Data Source: This was a randomized, open-label, multicenter, controlled trial of 719 liver transplant recipients testing the addition of everolimus with or without the withdrawal of tacrolimus (4 months after transplant) or tacrolimus alone.
Disclosures: The study was sponsored by Novartis, which manufactures everolimus. Dr. Saliba reported financial ties to Novartis and Astellas Pharma (manufacturer of tacrolimus), as well as other companies that manufacture drugs used by liver transplant patients. Several other investigators reported financial ties to companies that manufacture antirejection drugs used in liver transplant patients, including Novartis. Three study investigators are employees of Novartis.
Antivirals Linked to Lower Risk of Liver Cancer Return
Using antiviral drugs after "curative" surgery for hepatitis B–related liver cancer may lower the risk of cancer recurrence, according to a Taiwanese study presented at the annual meeting of the American Association for the Study of Liver Diseases and simultaneously published online in JAMA.
The cumulative 6-year incidence of hepatocellular carcinoma (HCC) recurrence was significantly lower for patients who were treated with the nucleoside analogues lamivudine, entecavir, or telbivudine than it was for patients who weren’t given these agents.
Accordingly, overall 6-year mortality and disease-related mortality also were significantly lower, said Dr. Chun-Ying Wu of National Yang-Ming University, Taipei, and his associates (JAMA 2012;308:1906-13 [doi: 10.1001/2012.jama.11975]).
The investigators noted that their study could not definitively establish that these antiviral drugs caused the reductions in cancer recurrence and mortality, because no retrospective observational study can prove causality. But nucleoside analogues are known to be effective at suppressing hepatitis B virus (HBV) replication, ameliorating other HBV-related liver diseases, and reducing the risk of HCC in patients with chronic hepatitis or cirrhosis.
"Although it is generally accepted that HBV viral load plays an important role in HCC recurrence, studies regarding the effectiveness of nucleoside analogues in HCC recurrence have been very limited and have produced conflicting results," they said.
The investigators examined the issue using data from Taiwan’s National Health Insurance Research Database, which covers more than 99% of the country’s population of approximately 25 million. They identified all 4,569 inpatients with newly diagnosed HBV-related HCC who underwent "curative" liver resection during a 6-year period.
A total of 518 of these patients received lamivudine (159 patients), entecavir (292 patients), telbivudine (36 patients), or a combination of these antivirals (31 patients) for at least 90 days. The remaining 4,051 patients never received any nucleoside analogues.
The mean duration of antiviral therapy with these nucleoside analogues was 1.5 years. The patients were followed up until HCC recurrence, death, or the end of the 6-year study period.
After the data were adjusted to account for competing mortality, the cumulative rate of HCC recurrence was significantly lower for patients who received the nucleoside analogues (45.6%) than for those who did not (54.6%), the researchers said.
The unadjusted number needed to treat to achieve 1 less HCC recurrence within 6 years was 12. "This implies that use of nucleoside analogues in 12 HCC patients after liver resection is associated with 1 less HCC recurrence within 6 years," the investigators explained.
The overall cumulative 6-year mortality rate also was significantly lower (29.0%) in patients who received the nucleoside analogues than in those who did not (42.4%).
The unadjusted number needed to treat associated with 1 less death within 6 years was 8. "This implies that use of nucleoside analogues in 8 HCC patients after liver resection is associated with 1 less death within 6 years," Dr. Wu and his colleagues said.
Treatment with nucleoside analogues also was associated with improved disease-free survival.
These results were unchanged when the data were analyzed according to the use or nonuse of NSAIDs and the presence or absence of comorbid diabetes.
However, the use of nucleoside analogues was associated with a lower risk of HCC recurrence in patients who didn’t have concomitant cirrhosis but not in those who did have cirrhosis, they noted.
This study was supported by Taiwan’s National Health Research Institute. No financial conflicts of interest were reported.
The researchers show that nucleoside analogues may reduce short-term mortality after liver resection, but "given the long interval between cell damage, malignant transformation, and tumor development, it is unrealistic to expect that administration of antiviral therapy for 1-2 years can prevent HCC recurrence," said Dr. Anna S. F. Lok.
"Further studies with longer duration of treatment and better characterization of HBV replication status and liver disease are needed to determine the magnitude of benefit" from taking the drugs, she said.
Dr. Lok is in the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. She reported serving as an adviser for Arrowhead, Bayer, and other companies, and receiving research grants from Bristol-Myers Squibb, Gilead, and GlaxoSmithKline. These remarks were taken from her editorial accompanying Dr. Wu’s report (JAMA 2012;308:1922-24 [doi: 10.1001/jama.2012.12971]).
cancer recurrence,
The researchers show that nucleoside analogues may reduce short-term mortality after liver resection, but "given the long interval between cell damage, malignant transformation, and tumor development, it is unrealistic to expect that administration of antiviral therapy for 1-2 years can prevent HCC recurrence," said Dr. Anna S. F. Lok.
"Further studies with longer duration of treatment and better characterization of HBV replication status and liver disease are needed to determine the magnitude of benefit" from taking the drugs, she said.
Dr. Lok is in the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. She reported serving as an adviser for Arrowhead, Bayer, and other companies, and receiving research grants from Bristol-Myers Squibb, Gilead, and GlaxoSmithKline. These remarks were taken from her editorial accompanying Dr. Wu’s report (JAMA 2012;308:1922-24 [doi: 10.1001/jama.2012.12971]).
The researchers show that nucleoside analogues may reduce short-term mortality after liver resection, but "given the long interval between cell damage, malignant transformation, and tumor development, it is unrealistic to expect that administration of antiviral therapy for 1-2 years can prevent HCC recurrence," said Dr. Anna S. F. Lok.
"Further studies with longer duration of treatment and better characterization of HBV replication status and liver disease are needed to determine the magnitude of benefit" from taking the drugs, she said.
Dr. Lok is in the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor. She reported serving as an adviser for Arrowhead, Bayer, and other companies, and receiving research grants from Bristol-Myers Squibb, Gilead, and GlaxoSmithKline. These remarks were taken from her editorial accompanying Dr. Wu’s report (JAMA 2012;308:1922-24 [doi: 10.1001/jama.2012.12971]).
Using antiviral drugs after "curative" surgery for hepatitis B–related liver cancer may lower the risk of cancer recurrence, according to a Taiwanese study presented at the annual meeting of the American Association for the Study of Liver Diseases and simultaneously published online in JAMA.
The cumulative 6-year incidence of hepatocellular carcinoma (HCC) recurrence was significantly lower for patients who were treated with the nucleoside analogues lamivudine, entecavir, or telbivudine than it was for patients who weren’t given these agents.
Accordingly, overall 6-year mortality and disease-related mortality also were significantly lower, said Dr. Chun-Ying Wu of National Yang-Ming University, Taipei, and his associates (JAMA 2012;308:1906-13 [doi: 10.1001/2012.jama.11975]).
The investigators noted that their study could not definitively establish that these antiviral drugs caused the reductions in cancer recurrence and mortality, because no retrospective observational study can prove causality. But nucleoside analogues are known to be effective at suppressing hepatitis B virus (HBV) replication, ameliorating other HBV-related liver diseases, and reducing the risk of HCC in patients with chronic hepatitis or cirrhosis.
"Although it is generally accepted that HBV viral load plays an important role in HCC recurrence, studies regarding the effectiveness of nucleoside analogues in HCC recurrence have been very limited and have produced conflicting results," they said.
The investigators examined the issue using data from Taiwan’s National Health Insurance Research Database, which covers more than 99% of the country’s population of approximately 25 million. They identified all 4,569 inpatients with newly diagnosed HBV-related HCC who underwent "curative" liver resection during a 6-year period.
A total of 518 of these patients received lamivudine (159 patients), entecavir (292 patients), telbivudine (36 patients), or a combination of these antivirals (31 patients) for at least 90 days. The remaining 4,051 patients never received any nucleoside analogues.
The mean duration of antiviral therapy with these nucleoside analogues was 1.5 years. The patients were followed up until HCC recurrence, death, or the end of the 6-year study period.
After the data were adjusted to account for competing mortality, the cumulative rate of HCC recurrence was significantly lower for patients who received the nucleoside analogues (45.6%) than for those who did not (54.6%), the researchers said.
The unadjusted number needed to treat to achieve 1 less HCC recurrence within 6 years was 12. "This implies that use of nucleoside analogues in 12 HCC patients after liver resection is associated with 1 less HCC recurrence within 6 years," the investigators explained.
The overall cumulative 6-year mortality rate also was significantly lower (29.0%) in patients who received the nucleoside analogues than in those who did not (42.4%).
The unadjusted number needed to treat associated with 1 less death within 6 years was 8. "This implies that use of nucleoside analogues in 8 HCC patients after liver resection is associated with 1 less death within 6 years," Dr. Wu and his colleagues said.
Treatment with nucleoside analogues also was associated with improved disease-free survival.
These results were unchanged when the data were analyzed according to the use or nonuse of NSAIDs and the presence or absence of comorbid diabetes.
However, the use of nucleoside analogues was associated with a lower risk of HCC recurrence in patients who didn’t have concomitant cirrhosis but not in those who did have cirrhosis, they noted.
This study was supported by Taiwan’s National Health Research Institute. No financial conflicts of interest were reported.
Using antiviral drugs after "curative" surgery for hepatitis B–related liver cancer may lower the risk of cancer recurrence, according to a Taiwanese study presented at the annual meeting of the American Association for the Study of Liver Diseases and simultaneously published online in JAMA.
The cumulative 6-year incidence of hepatocellular carcinoma (HCC) recurrence was significantly lower for patients who were treated with the nucleoside analogues lamivudine, entecavir, or telbivudine than it was for patients who weren’t given these agents.
Accordingly, overall 6-year mortality and disease-related mortality also were significantly lower, said Dr. Chun-Ying Wu of National Yang-Ming University, Taipei, and his associates (JAMA 2012;308:1906-13 [doi: 10.1001/2012.jama.11975]).
The investigators noted that their study could not definitively establish that these antiviral drugs caused the reductions in cancer recurrence and mortality, because no retrospective observational study can prove causality. But nucleoside analogues are known to be effective at suppressing hepatitis B virus (HBV) replication, ameliorating other HBV-related liver diseases, and reducing the risk of HCC in patients with chronic hepatitis or cirrhosis.
"Although it is generally accepted that HBV viral load plays an important role in HCC recurrence, studies regarding the effectiveness of nucleoside analogues in HCC recurrence have been very limited and have produced conflicting results," they said.
The investigators examined the issue using data from Taiwan’s National Health Insurance Research Database, which covers more than 99% of the country’s population of approximately 25 million. They identified all 4,569 inpatients with newly diagnosed HBV-related HCC who underwent "curative" liver resection during a 6-year period.
A total of 518 of these patients received lamivudine (159 patients), entecavir (292 patients), telbivudine (36 patients), or a combination of these antivirals (31 patients) for at least 90 days. The remaining 4,051 patients never received any nucleoside analogues.
The mean duration of antiviral therapy with these nucleoside analogues was 1.5 years. The patients were followed up until HCC recurrence, death, or the end of the 6-year study period.
After the data were adjusted to account for competing mortality, the cumulative rate of HCC recurrence was significantly lower for patients who received the nucleoside analogues (45.6%) than for those who did not (54.6%), the researchers said.
The unadjusted number needed to treat to achieve 1 less HCC recurrence within 6 years was 12. "This implies that use of nucleoside analogues in 12 HCC patients after liver resection is associated with 1 less HCC recurrence within 6 years," the investigators explained.
The overall cumulative 6-year mortality rate also was significantly lower (29.0%) in patients who received the nucleoside analogues than in those who did not (42.4%).
The unadjusted number needed to treat associated with 1 less death within 6 years was 8. "This implies that use of nucleoside analogues in 8 HCC patients after liver resection is associated with 1 less death within 6 years," Dr. Wu and his colleagues said.
Treatment with nucleoside analogues also was associated with improved disease-free survival.
These results were unchanged when the data were analyzed according to the use or nonuse of NSAIDs and the presence or absence of comorbid diabetes.
However, the use of nucleoside analogues was associated with a lower risk of HCC recurrence in patients who didn’t have concomitant cirrhosis but not in those who did have cirrhosis, they noted.
This study was supported by Taiwan’s National Health Research Institute. No financial conflicts of interest were reported.
cancer recurrence,
cancer recurrence,
FROM THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
Major Finding: The cumulative 6-year rate of hepatocellular carcinoma recurrence was 45.6% for patients taking nucleoside analogues and 54.6% for those not taking the drugs, and overall cumulative mortality was 29.0% and 42.4%, respectively.
Data Source: This was a retrospective observational study of patients with newly diagnosed hepatitis B virus–associated HCC who underwent liver resection and were followed for 6 years for the development of HCC recurrence, of whom 518 received antiviral therapy with nucleoside analogues and 4,051 did not.
Disclosures: This study was supported by Taiwan’s National Health Research Institute. No financial conflicts of interest were reported.
Acetaminophen-Linked Liver Failure Risk Heightened in Bariatric Surgery Patients
BOSTON – Prior bariatric surgery appears to be an independent risk factor for acetaminophen-related acute liver failure or injury, investigators reported at the annual meeting of the American Association for the Study of Liver Diseases.
A retrospective study of patients with acute liver failure (ALF) showed that 9 of 54 (17%) patients with ALF attributed to acetaminophen (APAP-ALF) had previously had bariatric surgery, compared with none of 47 patients with ALF from other causes, said Dr. Edward W. Holt, a researcher at the California Pacific Medical Center in San Francisco.
Although previous studies have shown associations between bariatric surgery and between alcohol abuse and APAP-ALF, they found that there were no significant differences in rates of suicidal ideation, depression, or alcohol abuse between patients who underwent bariatric surgery and those who had not, suggesting that bariatric surgery itself was a risk factor, Dr. Holt said.
"We feel that the implications of these findings are important," he said. "If validated in a larger cohort, our novel finding may identify a new group of patients at higher risk for APAP-ALF. If validated, additional warnings for patients with prior bariatric surgery may be warranted, similar to those currently in place for patients who consume three or more alcoholic drinks daily."
Possible explanations for the association include higher peak serum concentrations of ethanol after a challenge in patients who have undergone bariatric surgery, as well as higher rates of suicidal behaviors among these patients, compared with controls.
The investigators retrospectively reviewed data from their center on a prospectively identified cohort of 101 patients with acute liver failure from acetaminophen and other causes, including drug-induced, infections, lymphoma, ischemia, and heatstroke. Of the 54 patients with APAP-ALF, 8 had undergone roux-en-Y gastric bypass, and one had a duodenal switch procedure, at a mean of nearly 6 years before diagnosis of ALF.
Among the patients in the APAP-ALF group, the prevalence of bariatric surgery was 25.3-fold higher than the estimated prevalence in the general population (16.7% vs. 0.5%; estimate based on published literature and national hospital discharge data).
The patients with APAP-ALF and ALF from other causes were similar in age, but there were more women (P = .02) and whites (P less than .0001) in the APAP-ALF group, and patients in this group had significantly fewer deaths (P less than .0006) and transplants (P less than .0001).
When the researchers looked at possible risk factors for ALF, they found that patients in the ALF/other group had significantly lower frequencies of depression (P less than .001), alcohol abuse (P = .01), and acetaminophen-containing combination analgesics (P less than .0001). But when they compared patients with or without bariatric surgery, there were no significant differences in any of the variables mentioned above.
Dr. Holt noted that the study was limited by its single-center design, inability to test proposed mechanisms for the increased risk seen in patients who had undergone bariatric surgery (such as changes in glutathione levels), and the inability to perform a logistic regression analysis, as none of the patients with non-APAP ALF had undergone surgery.
In the question-and-response portion following his presentation, Dr. Holt was asked whether liver biopsies had been performed to see if patients had background steatohepatitis or fibrosis that might account for the results, and whether body mass index data were available.
He noted that the patients came primarily from his institution’s wide referral base, and they therefore did not have all the demographic or clinical information about each patient that they would have liked.
The study was internally funded. Dr. Holt reported no relevant financial disclosures.
BOSTON – Prior bariatric surgery appears to be an independent risk factor for acetaminophen-related acute liver failure or injury, investigators reported at the annual meeting of the American Association for the Study of Liver Diseases.
A retrospective study of patients with acute liver failure (ALF) showed that 9 of 54 (17%) patients with ALF attributed to acetaminophen (APAP-ALF) had previously had bariatric surgery, compared with none of 47 patients with ALF from other causes, said Dr. Edward W. Holt, a researcher at the California Pacific Medical Center in San Francisco.
Although previous studies have shown associations between bariatric surgery and between alcohol abuse and APAP-ALF, they found that there were no significant differences in rates of suicidal ideation, depression, or alcohol abuse between patients who underwent bariatric surgery and those who had not, suggesting that bariatric surgery itself was a risk factor, Dr. Holt said.
"We feel that the implications of these findings are important," he said. "If validated in a larger cohort, our novel finding may identify a new group of patients at higher risk for APAP-ALF. If validated, additional warnings for patients with prior bariatric surgery may be warranted, similar to those currently in place for patients who consume three or more alcoholic drinks daily."
Possible explanations for the association include higher peak serum concentrations of ethanol after a challenge in patients who have undergone bariatric surgery, as well as higher rates of suicidal behaviors among these patients, compared with controls.
The investigators retrospectively reviewed data from their center on a prospectively identified cohort of 101 patients with acute liver failure from acetaminophen and other causes, including drug-induced, infections, lymphoma, ischemia, and heatstroke. Of the 54 patients with APAP-ALF, 8 had undergone roux-en-Y gastric bypass, and one had a duodenal switch procedure, at a mean of nearly 6 years before diagnosis of ALF.
Among the patients in the APAP-ALF group, the prevalence of bariatric surgery was 25.3-fold higher than the estimated prevalence in the general population (16.7% vs. 0.5%; estimate based on published literature and national hospital discharge data).
The patients with APAP-ALF and ALF from other causes were similar in age, but there were more women (P = .02) and whites (P less than .0001) in the APAP-ALF group, and patients in this group had significantly fewer deaths (P less than .0006) and transplants (P less than .0001).
When the researchers looked at possible risk factors for ALF, they found that patients in the ALF/other group had significantly lower frequencies of depression (P less than .001), alcohol abuse (P = .01), and acetaminophen-containing combination analgesics (P less than .0001). But when they compared patients with or without bariatric surgery, there were no significant differences in any of the variables mentioned above.
Dr. Holt noted that the study was limited by its single-center design, inability to test proposed mechanisms for the increased risk seen in patients who had undergone bariatric surgery (such as changes in glutathione levels), and the inability to perform a logistic regression analysis, as none of the patients with non-APAP ALF had undergone surgery.
In the question-and-response portion following his presentation, Dr. Holt was asked whether liver biopsies had been performed to see if patients had background steatohepatitis or fibrosis that might account for the results, and whether body mass index data were available.
He noted that the patients came primarily from his institution’s wide referral base, and they therefore did not have all the demographic or clinical information about each patient that they would have liked.
The study was internally funded. Dr. Holt reported no relevant financial disclosures.
BOSTON – Prior bariatric surgery appears to be an independent risk factor for acetaminophen-related acute liver failure or injury, investigators reported at the annual meeting of the American Association for the Study of Liver Diseases.
A retrospective study of patients with acute liver failure (ALF) showed that 9 of 54 (17%) patients with ALF attributed to acetaminophen (APAP-ALF) had previously had bariatric surgery, compared with none of 47 patients with ALF from other causes, said Dr. Edward W. Holt, a researcher at the California Pacific Medical Center in San Francisco.
Although previous studies have shown associations between bariatric surgery and between alcohol abuse and APAP-ALF, they found that there were no significant differences in rates of suicidal ideation, depression, or alcohol abuse between patients who underwent bariatric surgery and those who had not, suggesting that bariatric surgery itself was a risk factor, Dr. Holt said.
"We feel that the implications of these findings are important," he said. "If validated in a larger cohort, our novel finding may identify a new group of patients at higher risk for APAP-ALF. If validated, additional warnings for patients with prior bariatric surgery may be warranted, similar to those currently in place for patients who consume three or more alcoholic drinks daily."
Possible explanations for the association include higher peak serum concentrations of ethanol after a challenge in patients who have undergone bariatric surgery, as well as higher rates of suicidal behaviors among these patients, compared with controls.
The investigators retrospectively reviewed data from their center on a prospectively identified cohort of 101 patients with acute liver failure from acetaminophen and other causes, including drug-induced, infections, lymphoma, ischemia, and heatstroke. Of the 54 patients with APAP-ALF, 8 had undergone roux-en-Y gastric bypass, and one had a duodenal switch procedure, at a mean of nearly 6 years before diagnosis of ALF.
Among the patients in the APAP-ALF group, the prevalence of bariatric surgery was 25.3-fold higher than the estimated prevalence in the general population (16.7% vs. 0.5%; estimate based on published literature and national hospital discharge data).
The patients with APAP-ALF and ALF from other causes were similar in age, but there were more women (P = .02) and whites (P less than .0001) in the APAP-ALF group, and patients in this group had significantly fewer deaths (P less than .0006) and transplants (P less than .0001).
When the researchers looked at possible risk factors for ALF, they found that patients in the ALF/other group had significantly lower frequencies of depression (P less than .001), alcohol abuse (P = .01), and acetaminophen-containing combination analgesics (P less than .0001). But when they compared patients with or without bariatric surgery, there were no significant differences in any of the variables mentioned above.
Dr. Holt noted that the study was limited by its single-center design, inability to test proposed mechanisms for the increased risk seen in patients who had undergone bariatric surgery (such as changes in glutathione levels), and the inability to perform a logistic regression analysis, as none of the patients with non-APAP ALF had undergone surgery.
In the question-and-response portion following his presentation, Dr. Holt was asked whether liver biopsies had been performed to see if patients had background steatohepatitis or fibrosis that might account for the results, and whether body mass index data were available.
He noted that the patients came primarily from his institution’s wide referral base, and they therefore did not have all the demographic or clinical information about each patient that they would have liked.
The study was internally funded. Dr. Holt reported no relevant financial disclosures.
AT THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
Major Finding: Among patients with acute liver failure from acetaminophen, the prevalence of prior bariatric surgery was 25-fold higher than in the general population, suggesting bariatric surgery may be a risk factor for liver failure.
Data Source: This was a retrospective cohort study of 101 patients with liver failure from various causes.
Disclosures: The study was internally funded. Dr. Holt reported no relevant financial disclosures.
Benefit of Young Liver Donors Scrutinized in Study
BOSTON – Younger age of deceased liver donors appeared to improve patient and graft survival when donors and recipients were both of younger age, but not when younger donor livers went to older recipients, according to a secondary analysis of the Organ Procurement and Transplantation Network national database from 2002 to 2011.
"Matching younger recipients with younger donors appears to be the best strategy in order to maximize life years after liver transplantation. However, before this can be considered for allocation policy, much more work needs to be done," including analyses specific to United Network for Organ Sharing regions, Model for End-Stage Liver Disease groups, and modeling of the potential life-years saved with a change in allocation policy, said lead investigator Dr. Neehar D. Parikh of the Comprehensive Transplant Center at Northwestern University, Chicago.
The risk of recipient death is known to increase with advancing donor age, beginning at ages older than 40 years and especially with donors older than 60 years. Also, advancing recipient age has been shown, with some controversy, to affect outcomes negatively, Dr. Parikh said at the annual meeting of the American Association for the Study of Liver Diseases.
Dr. Parikh and his colleagues’ study of the Organ Procurement and Transplantation Network database analyzed 26,849 cases of liver transplantation in which the donor was younger than the recipient, 782 cases in which they were the same age, and 12,107 cases in which the donor was older than the recipient. They also looked at outcomes of patients aged 18-40 years and those 60 years or older, based on the donor age.
As would be expected, recipients had progressively younger mean ages as the donor age increased: 56 years for recipients with younger donors, 52 years for same-age donors, and 48 years for older donors. Hepatitis C virus seropositivity was lowest in recipients who had an older donor (41%), followed by same-age recipient-donor pairs (51%), and recipients who had a younger donor (50%).
In Kaplan-Meier analyses, patient survival at 1 year was significantly worse for those who received a liver from a donor with an older age (86%) or the same age (86%) than from a younger donor (87.4%). Similar results were seen at 3 years between recipients of livers from older (74.5%), same age (73.5%), and younger donors (77.9%).
Older donor age increased the risk for patient death by 14% and graft failure by 13%, in comparison with younger donor age in an adjusted analysis.
For every 10-year increase in patient age for younger donors, the risk of patient mortality increased by 24% and graft failure by 17%. For every 10 years the donor was younger than the recipient, however, there was a 27% decline in the risk of patient mortality and 30% decrease in the risk of graft failure. A small but significance beneficial interaction was found between young donor age and young recipient age on both outcomes.
In contrast, for every 10 years the donor was older than the recipient, the risk of patient mortality increased 9% and the risk of graft failure increased by 22%, and there was no significant interaction between recipient and donor age.
When compared against donor and recipient pairs who were both aged 18-40 years, the risk of patient mortality and graft failure increased significantly for all other combinations of donor and recipient pairs: recipients aged 18-40 years and donors aged 60 years or older (hazard ratios of 1.76 and 1.49, respectively), recipients aged 60 years older and donors aged 18-40 years (HRs of 1.67 and 1.83), and recipients and donors both aged 60 years or older (HRs of 2.12 and 1.87). These results were consistent at both 1 and 3 years.
The overall results "suggest that there is something intrinsic about being older or having an older graft that cannot be remediated by graft or patient age factors," Dr. Parikh said.
The results might be explained in livers from older donors by impaired liver regeneration and increased susceptibility to ischemic reperfusion injury, while older recipients might have decreased circulating stem cells and more competing risks that are not adequately risk adjusted in the available data in older recipients, he said.
One audience member noted that there is still a "huge survival advantage" in all patient populations that receive younger donor livers and that allocating organs based on age is a slippery slope.
Dr. Parikh and his colleagues had no relevant financial disclosures.
BOSTON – Younger age of deceased liver donors appeared to improve patient and graft survival when donors and recipients were both of younger age, but not when younger donor livers went to older recipients, according to a secondary analysis of the Organ Procurement and Transplantation Network national database from 2002 to 2011.
"Matching younger recipients with younger donors appears to be the best strategy in order to maximize life years after liver transplantation. However, before this can be considered for allocation policy, much more work needs to be done," including analyses specific to United Network for Organ Sharing regions, Model for End-Stage Liver Disease groups, and modeling of the potential life-years saved with a change in allocation policy, said lead investigator Dr. Neehar D. Parikh of the Comprehensive Transplant Center at Northwestern University, Chicago.
The risk of recipient death is known to increase with advancing donor age, beginning at ages older than 40 years and especially with donors older than 60 years. Also, advancing recipient age has been shown, with some controversy, to affect outcomes negatively, Dr. Parikh said at the annual meeting of the American Association for the Study of Liver Diseases.
Dr. Parikh and his colleagues’ study of the Organ Procurement and Transplantation Network database analyzed 26,849 cases of liver transplantation in which the donor was younger than the recipient, 782 cases in which they were the same age, and 12,107 cases in which the donor was older than the recipient. They also looked at outcomes of patients aged 18-40 years and those 60 years or older, based on the donor age.
As would be expected, recipients had progressively younger mean ages as the donor age increased: 56 years for recipients with younger donors, 52 years for same-age donors, and 48 years for older donors. Hepatitis C virus seropositivity was lowest in recipients who had an older donor (41%), followed by same-age recipient-donor pairs (51%), and recipients who had a younger donor (50%).
In Kaplan-Meier analyses, patient survival at 1 year was significantly worse for those who received a liver from a donor with an older age (86%) or the same age (86%) than from a younger donor (87.4%). Similar results were seen at 3 years between recipients of livers from older (74.5%), same age (73.5%), and younger donors (77.9%).
Older donor age increased the risk for patient death by 14% and graft failure by 13%, in comparison with younger donor age in an adjusted analysis.
For every 10-year increase in patient age for younger donors, the risk of patient mortality increased by 24% and graft failure by 17%. For every 10 years the donor was younger than the recipient, however, there was a 27% decline in the risk of patient mortality and 30% decrease in the risk of graft failure. A small but significance beneficial interaction was found between young donor age and young recipient age on both outcomes.
In contrast, for every 10 years the donor was older than the recipient, the risk of patient mortality increased 9% and the risk of graft failure increased by 22%, and there was no significant interaction between recipient and donor age.
When compared against donor and recipient pairs who were both aged 18-40 years, the risk of patient mortality and graft failure increased significantly for all other combinations of donor and recipient pairs: recipients aged 18-40 years and donors aged 60 years or older (hazard ratios of 1.76 and 1.49, respectively), recipients aged 60 years older and donors aged 18-40 years (HRs of 1.67 and 1.83), and recipients and donors both aged 60 years or older (HRs of 2.12 and 1.87). These results were consistent at both 1 and 3 years.
The overall results "suggest that there is something intrinsic about being older or having an older graft that cannot be remediated by graft or patient age factors," Dr. Parikh said.
The results might be explained in livers from older donors by impaired liver regeneration and increased susceptibility to ischemic reperfusion injury, while older recipients might have decreased circulating stem cells and more competing risks that are not adequately risk adjusted in the available data in older recipients, he said.
One audience member noted that there is still a "huge survival advantage" in all patient populations that receive younger donor livers and that allocating organs based on age is a slippery slope.
Dr. Parikh and his colleagues had no relevant financial disclosures.
BOSTON – Younger age of deceased liver donors appeared to improve patient and graft survival when donors and recipients were both of younger age, but not when younger donor livers went to older recipients, according to a secondary analysis of the Organ Procurement and Transplantation Network national database from 2002 to 2011.
"Matching younger recipients with younger donors appears to be the best strategy in order to maximize life years after liver transplantation. However, before this can be considered for allocation policy, much more work needs to be done," including analyses specific to United Network for Organ Sharing regions, Model for End-Stage Liver Disease groups, and modeling of the potential life-years saved with a change in allocation policy, said lead investigator Dr. Neehar D. Parikh of the Comprehensive Transplant Center at Northwestern University, Chicago.
The risk of recipient death is known to increase with advancing donor age, beginning at ages older than 40 years and especially with donors older than 60 years. Also, advancing recipient age has been shown, with some controversy, to affect outcomes negatively, Dr. Parikh said at the annual meeting of the American Association for the Study of Liver Diseases.
Dr. Parikh and his colleagues’ study of the Organ Procurement and Transplantation Network database analyzed 26,849 cases of liver transplantation in which the donor was younger than the recipient, 782 cases in which they were the same age, and 12,107 cases in which the donor was older than the recipient. They also looked at outcomes of patients aged 18-40 years and those 60 years or older, based on the donor age.
As would be expected, recipients had progressively younger mean ages as the donor age increased: 56 years for recipients with younger donors, 52 years for same-age donors, and 48 years for older donors. Hepatitis C virus seropositivity was lowest in recipients who had an older donor (41%), followed by same-age recipient-donor pairs (51%), and recipients who had a younger donor (50%).
In Kaplan-Meier analyses, patient survival at 1 year was significantly worse for those who received a liver from a donor with an older age (86%) or the same age (86%) than from a younger donor (87.4%). Similar results were seen at 3 years between recipients of livers from older (74.5%), same age (73.5%), and younger donors (77.9%).
Older donor age increased the risk for patient death by 14% and graft failure by 13%, in comparison with younger donor age in an adjusted analysis.
For every 10-year increase in patient age for younger donors, the risk of patient mortality increased by 24% and graft failure by 17%. For every 10 years the donor was younger than the recipient, however, there was a 27% decline in the risk of patient mortality and 30% decrease in the risk of graft failure. A small but significance beneficial interaction was found between young donor age and young recipient age on both outcomes.
In contrast, for every 10 years the donor was older than the recipient, the risk of patient mortality increased 9% and the risk of graft failure increased by 22%, and there was no significant interaction between recipient and donor age.
When compared against donor and recipient pairs who were both aged 18-40 years, the risk of patient mortality and graft failure increased significantly for all other combinations of donor and recipient pairs: recipients aged 18-40 years and donors aged 60 years or older (hazard ratios of 1.76 and 1.49, respectively), recipients aged 60 years older and donors aged 18-40 years (HRs of 1.67 and 1.83), and recipients and donors both aged 60 years or older (HRs of 2.12 and 1.87). These results were consistent at both 1 and 3 years.
The overall results "suggest that there is something intrinsic about being older or having an older graft that cannot be remediated by graft or patient age factors," Dr. Parikh said.
The results might be explained in livers from older donors by impaired liver regeneration and increased susceptibility to ischemic reperfusion injury, while older recipients might have decreased circulating stem cells and more competing risks that are not adequately risk adjusted in the available data in older recipients, he said.
One audience member noted that there is still a "huge survival advantage" in all patient populations that receive younger donor livers and that allocating organs based on age is a slippery slope.
Dr. Parikh and his colleagues had no relevant financial disclosures.
AT THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
Major Finding: For every 10-year increase in patient age for younger donors, the risk of patient mortality increased by 24% and graft failure by 17%; for every 10 years the donor was younger than the recipient, there was a 27% decline in the risk of patient mortality and a 30% decrease in the risk of graft failure.
Data Source: This was a secondary analysis of the Organ Procurement and Transplantation Network national database from 2002 to 2011 for adult cadaveric liver transplantation.
Disclosures: Dr. Parikh and his colleagues had no relevant financial disclosures.
Acetaminophen Liver Failure Least Likely to Get Transplant
BOSTON – Acetaminophen toxicity is the most frequent cause of acute liver failure in the United States and its usually milder presentation, along with comorbid psychosocial issues, explain why fewer patients with the etiology undergo liver transplantation, compared with other causes, according to a 10-year retrospective study of the National Institute of Diabetes and Digestive and Kidney Diseases Acute Liver Failure database.
Dr. K. Rajender Reddy and his colleagues in the National Institutes of Health Acute Liver Failure Study Group set out to determine factors that could help clinicians to improve their selection of acute liver failure patients for liver transplantation listing and their decision to proceed with transplantation.
At the annual meeting of the American Association for the Study of Liver Diseases, Dr. Reddy reported that of 1,144 patients who had at least 1 year of follow-up in the database, 491 (43%) had an acetaminophen etiology for acute liver failure, but only 26% of all patients listed for transplantation had an acetaminophen etiology and just 14% of all transplants occurred in patients with acetaminophen toxicity as the underlying cause.
In comparison, patients with other etiologies had higher listing and transplantation rates, with the highest being for autoimmune hepatitis (62% of all patients listed and 50% of all transplanted).
Overall during 2000-2010, 697 patients were not listed and not transplanted (group A), 177 were listed and not transplanted (group B), and 270 were listed and transplanted (group C). After 2 years of follow-up, patient survival was highest in group C (82%), followed by group A (47%) and group B (41%). Survival at 21 days followed the same pattern (C, 89%; A, 58%; B, 45%). Patients in groups A and B with acetaminophen etiology had greater 21-day survival than did those without an acetaminophen etiology.
Patients in group A had significantly higher rates of positive toxicology screens than did groups B and C (43% vs. 35% and 19%, respectively) and history of illicit drug use (10% vs. 4% and 2%).
Comparisons between patients who died in group B and all patients in group C could not find significant risk factors to explain the higher mortality in group B, including longer wait list times and variations in survival and transplant rates by geographic location, although greater coma severity may have contributed to the higher mortality, said Dr. Reddy, professor of medicine in the division of gastroenterology at the Hospital of the University of Pennsylvania, Philadelphia.
Dr. Reddy said that he had no relevant financial disclosures. The study was funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases to the National Institutes of Health Acute Liver Failure Study Group.
BOSTON – Acetaminophen toxicity is the most frequent cause of acute liver failure in the United States and its usually milder presentation, along with comorbid psychosocial issues, explain why fewer patients with the etiology undergo liver transplantation, compared with other causes, according to a 10-year retrospective study of the National Institute of Diabetes and Digestive and Kidney Diseases Acute Liver Failure database.
Dr. K. Rajender Reddy and his colleagues in the National Institutes of Health Acute Liver Failure Study Group set out to determine factors that could help clinicians to improve their selection of acute liver failure patients for liver transplantation listing and their decision to proceed with transplantation.
At the annual meeting of the American Association for the Study of Liver Diseases, Dr. Reddy reported that of 1,144 patients who had at least 1 year of follow-up in the database, 491 (43%) had an acetaminophen etiology for acute liver failure, but only 26% of all patients listed for transplantation had an acetaminophen etiology and just 14% of all transplants occurred in patients with acetaminophen toxicity as the underlying cause.
In comparison, patients with other etiologies had higher listing and transplantation rates, with the highest being for autoimmune hepatitis (62% of all patients listed and 50% of all transplanted).
Overall during 2000-2010, 697 patients were not listed and not transplanted (group A), 177 were listed and not transplanted (group B), and 270 were listed and transplanted (group C). After 2 years of follow-up, patient survival was highest in group C (82%), followed by group A (47%) and group B (41%). Survival at 21 days followed the same pattern (C, 89%; A, 58%; B, 45%). Patients in groups A and B with acetaminophen etiology had greater 21-day survival than did those without an acetaminophen etiology.
Patients in group A had significantly higher rates of positive toxicology screens than did groups B and C (43% vs. 35% and 19%, respectively) and history of illicit drug use (10% vs. 4% and 2%).
Comparisons between patients who died in group B and all patients in group C could not find significant risk factors to explain the higher mortality in group B, including longer wait list times and variations in survival and transplant rates by geographic location, although greater coma severity may have contributed to the higher mortality, said Dr. Reddy, professor of medicine in the division of gastroenterology at the Hospital of the University of Pennsylvania, Philadelphia.
Dr. Reddy said that he had no relevant financial disclosures. The study was funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases to the National Institutes of Health Acute Liver Failure Study Group.
BOSTON – Acetaminophen toxicity is the most frequent cause of acute liver failure in the United States and its usually milder presentation, along with comorbid psychosocial issues, explain why fewer patients with the etiology undergo liver transplantation, compared with other causes, according to a 10-year retrospective study of the National Institute of Diabetes and Digestive and Kidney Diseases Acute Liver Failure database.
Dr. K. Rajender Reddy and his colleagues in the National Institutes of Health Acute Liver Failure Study Group set out to determine factors that could help clinicians to improve their selection of acute liver failure patients for liver transplantation listing and their decision to proceed with transplantation.
At the annual meeting of the American Association for the Study of Liver Diseases, Dr. Reddy reported that of 1,144 patients who had at least 1 year of follow-up in the database, 491 (43%) had an acetaminophen etiology for acute liver failure, but only 26% of all patients listed for transplantation had an acetaminophen etiology and just 14% of all transplants occurred in patients with acetaminophen toxicity as the underlying cause.
In comparison, patients with other etiologies had higher listing and transplantation rates, with the highest being for autoimmune hepatitis (62% of all patients listed and 50% of all transplanted).
Overall during 2000-2010, 697 patients were not listed and not transplanted (group A), 177 were listed and not transplanted (group B), and 270 were listed and transplanted (group C). After 2 years of follow-up, patient survival was highest in group C (82%), followed by group A (47%) and group B (41%). Survival at 21 days followed the same pattern (C, 89%; A, 58%; B, 45%). Patients in groups A and B with acetaminophen etiology had greater 21-day survival than did those without an acetaminophen etiology.
Patients in group A had significantly higher rates of positive toxicology screens than did groups B and C (43% vs. 35% and 19%, respectively) and history of illicit drug use (10% vs. 4% and 2%).
Comparisons between patients who died in group B and all patients in group C could not find significant risk factors to explain the higher mortality in group B, including longer wait list times and variations in survival and transplant rates by geographic location, although greater coma severity may have contributed to the higher mortality, said Dr. Reddy, professor of medicine in the division of gastroenterology at the Hospital of the University of Pennsylvania, Philadelphia.
Dr. Reddy said that he had no relevant financial disclosures. The study was funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases to the National Institutes of Health Acute Liver Failure Study Group.
AT THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
Major Finding: A total of 43% in the study had an acetaminophen etiology for acute liver failure, but only 26% of all patients listed for transplantation had an acetaminophen etiology and just 14% of all transplants occurred in patients with acetaminophen toxicity as the underlying cause.
Data Source: This was a 10-year retrospective study of the National Institute of Diabetes and Digestive and Kidney Diseases Acute Liver Failure database.
Disclosures: Dr. Reddy said he had no relevant financial disclosures. The study was funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases to the National Institutes of Health Acute Liver Failure Study Group.
Fatty Liver Disease Cited for Rise in Hepatocellular Carcinoma
BOSTON – Nonalcoholic fatty liver disease without cirrhosis appears to be a significant contributor to the rise in the incidence of hepatocellular carcinoma in the past two decades, according to a study linking population-based data from the National Cancer Institute with Medicare enrollment and claim files during 1993-2007.
"Our data suggest a unique underlying pathophysiology for development of HCC [hepatocellular carcinoma] in noncirrhotic NAFLD [nonalcoholic fatty liver disease]," Dr. Rubayat Rahman said at the annual meeting of the American Association for the Study of Liver Diseases.
The finding may help to explain the rise in the incidence of the malignancy, which has had no clear explanation, added Dr. Rahman of the division of gastroenterology and hepatology at the University of Missouri, Columbia.
Of 17,895 HCC cases in the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, 2,863 (16%) had only NAFLD without any other risk factors or etiologies for HCC. The linked database covers 30% of the U.S. Medicare population. SEER itself contains data from 18 cancer registries covering 28% of the U.S. population, and 93% of the individuals in the database who are at least 65 years are matched to a Medicare enrollment file.
At 16%, NAFLD was third most common risk factor for HCC after infection (44%) and alcoholic diseases (19%) – 21% were other causes – but it was the second most common risk factor after infection in Asians and Pacific islanders, said Dr. Rahman.
Cirrhosis was not present in 36% of the NAFLD-related HCC cases; of those, 18% had only steatosis and not nonalcoholic steatohepatitis (NASH) or other adverse changes in pathology. Patients without cirrhosis more often had early-stage disease (stage I or II) than did those with cirrhosis (62% vs. 44%), as well as favorable grades (I or II, 76% vs. 56%).
Although the annual percentage change of NAFLD-related HCC with cirrhosis has increased since 1993, 1999 marked a point when the annual growth of NAFLD-related cases of HCC without cirrhosis outpaced those with cirrhosis. The average number of cases per year of NAFLD-related HCC without cirrhosis grew significantly from 51 in 1993-2000 to 88 in 2001-2007, compared with no change in cases with cirrhosis.
Three components of the metabolic syndrome – body-mass index greater than 30 kg/m2, type 2 diabetes mellitus, and dyslipidemia – occurred in significantly greater proportions of patients with NAFLD-related HCC without cirrhosis than in those with cirrhosis. The odds of developing HCC for each of those three components among noncirrhotic NAFLD patients was higher than for those with cirrhotic NAFLD, although the overall odds of developing HCC were higher among patients with cirrhotic NAFLD (odds ratio, 16.5) than in those with noncirrhotic NAFLD (OR, 3.1).
One audience member expressed concern about determining the presence of cirrhosis or NASH in the data without a systematic assessment of histopathology performed in a centralized way, but Dr. Rahman noted that the Medicare-matched SEER data have CPT procedural codes and ICD-9 diagnostic codes for diagnoses made through liver biopsy. Another attendee also suggested caution in calling NAFLD a risk factor for cancer alone because the people in the database have a higher rate of cancer, and the database does not include the peak of NASH at age 55 years.
None of the study investigators had relevant financial disclosures.
BOSTON – Nonalcoholic fatty liver disease without cirrhosis appears to be a significant contributor to the rise in the incidence of hepatocellular carcinoma in the past two decades, according to a study linking population-based data from the National Cancer Institute with Medicare enrollment and claim files during 1993-2007.
"Our data suggest a unique underlying pathophysiology for development of HCC [hepatocellular carcinoma] in noncirrhotic NAFLD [nonalcoholic fatty liver disease]," Dr. Rubayat Rahman said at the annual meeting of the American Association for the Study of Liver Diseases.
The finding may help to explain the rise in the incidence of the malignancy, which has had no clear explanation, added Dr. Rahman of the division of gastroenterology and hepatology at the University of Missouri, Columbia.
Of 17,895 HCC cases in the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, 2,863 (16%) had only NAFLD without any other risk factors or etiologies for HCC. The linked database covers 30% of the U.S. Medicare population. SEER itself contains data from 18 cancer registries covering 28% of the U.S. population, and 93% of the individuals in the database who are at least 65 years are matched to a Medicare enrollment file.
At 16%, NAFLD was third most common risk factor for HCC after infection (44%) and alcoholic diseases (19%) – 21% were other causes – but it was the second most common risk factor after infection in Asians and Pacific islanders, said Dr. Rahman.
Cirrhosis was not present in 36% of the NAFLD-related HCC cases; of those, 18% had only steatosis and not nonalcoholic steatohepatitis (NASH) or other adverse changes in pathology. Patients without cirrhosis more often had early-stage disease (stage I or II) than did those with cirrhosis (62% vs. 44%), as well as favorable grades (I or II, 76% vs. 56%).
Although the annual percentage change of NAFLD-related HCC with cirrhosis has increased since 1993, 1999 marked a point when the annual growth of NAFLD-related cases of HCC without cirrhosis outpaced those with cirrhosis. The average number of cases per year of NAFLD-related HCC without cirrhosis grew significantly from 51 in 1993-2000 to 88 in 2001-2007, compared with no change in cases with cirrhosis.
Three components of the metabolic syndrome – body-mass index greater than 30 kg/m2, type 2 diabetes mellitus, and dyslipidemia – occurred in significantly greater proportions of patients with NAFLD-related HCC without cirrhosis than in those with cirrhosis. The odds of developing HCC for each of those three components among noncirrhotic NAFLD patients was higher than for those with cirrhotic NAFLD, although the overall odds of developing HCC were higher among patients with cirrhotic NAFLD (odds ratio, 16.5) than in those with noncirrhotic NAFLD (OR, 3.1).
One audience member expressed concern about determining the presence of cirrhosis or NASH in the data without a systematic assessment of histopathology performed in a centralized way, but Dr. Rahman noted that the Medicare-matched SEER data have CPT procedural codes and ICD-9 diagnostic codes for diagnoses made through liver biopsy. Another attendee also suggested caution in calling NAFLD a risk factor for cancer alone because the people in the database have a higher rate of cancer, and the database does not include the peak of NASH at age 55 years.
None of the study investigators had relevant financial disclosures.
BOSTON – Nonalcoholic fatty liver disease without cirrhosis appears to be a significant contributor to the rise in the incidence of hepatocellular carcinoma in the past two decades, according to a study linking population-based data from the National Cancer Institute with Medicare enrollment and claim files during 1993-2007.
"Our data suggest a unique underlying pathophysiology for development of HCC [hepatocellular carcinoma] in noncirrhotic NAFLD [nonalcoholic fatty liver disease]," Dr. Rubayat Rahman said at the annual meeting of the American Association for the Study of Liver Diseases.
The finding may help to explain the rise in the incidence of the malignancy, which has had no clear explanation, added Dr. Rahman of the division of gastroenterology and hepatology at the University of Missouri, Columbia.
Of 17,895 HCC cases in the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, 2,863 (16%) had only NAFLD without any other risk factors or etiologies for HCC. The linked database covers 30% of the U.S. Medicare population. SEER itself contains data from 18 cancer registries covering 28% of the U.S. population, and 93% of the individuals in the database who are at least 65 years are matched to a Medicare enrollment file.
At 16%, NAFLD was third most common risk factor for HCC after infection (44%) and alcoholic diseases (19%) – 21% were other causes – but it was the second most common risk factor after infection in Asians and Pacific islanders, said Dr. Rahman.
Cirrhosis was not present in 36% of the NAFLD-related HCC cases; of those, 18% had only steatosis and not nonalcoholic steatohepatitis (NASH) or other adverse changes in pathology. Patients without cirrhosis more often had early-stage disease (stage I or II) than did those with cirrhosis (62% vs. 44%), as well as favorable grades (I or II, 76% vs. 56%).
Although the annual percentage change of NAFLD-related HCC with cirrhosis has increased since 1993, 1999 marked a point when the annual growth of NAFLD-related cases of HCC without cirrhosis outpaced those with cirrhosis. The average number of cases per year of NAFLD-related HCC without cirrhosis grew significantly from 51 in 1993-2000 to 88 in 2001-2007, compared with no change in cases with cirrhosis.
Three components of the metabolic syndrome – body-mass index greater than 30 kg/m2, type 2 diabetes mellitus, and dyslipidemia – occurred in significantly greater proportions of patients with NAFLD-related HCC without cirrhosis than in those with cirrhosis. The odds of developing HCC for each of those three components among noncirrhotic NAFLD patients was higher than for those with cirrhotic NAFLD, although the overall odds of developing HCC were higher among patients with cirrhotic NAFLD (odds ratio, 16.5) than in those with noncirrhotic NAFLD (OR, 3.1).
One audience member expressed concern about determining the presence of cirrhosis or NASH in the data without a systematic assessment of histopathology performed in a centralized way, but Dr. Rahman noted that the Medicare-matched SEER data have CPT procedural codes and ICD-9 diagnostic codes for diagnoses made through liver biopsy. Another attendee also suggested caution in calling NAFLD a risk factor for cancer alone because the people in the database have a higher rate of cancer, and the database does not include the peak of NASH at age 55 years.
None of the study investigators had relevant financial disclosures.
AT THE ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES
Major Finding: The average number of cases per year of NAFLD-related hepatocellular carcinoma without cirrhosis grew significantly from 51 in 1993-2000 to 88 in 2001-2007, compared with no change in cases with cirrhosis.
Data Source: This population-based study used data from the SEER-Medicare database from 1993 to 2007.
Disclosures: None of the study investigators had relevant financial disclosures.