An author of a new study associating the hypnotic zolpidem (Ambien) with higher rates of patient falls says hospitalists should keep the popular drug’s risks front of mind.

The retrospective cohort study in the Journal of Hospital Medicine, “Zolpidem is Independently Associated with Increased Risk of Inpatient Falls,” found that the rate of falls increased nearly six times among patients taking the sleep agent. The research team at the Center for Sleep Medicine at the Mayo Clinic in Rochester, N.Y., calculated one additional fall for every 55 admitted patients who were administered the treatment.

“What this says to me is if one is going to use zolpidem, you have to be aware you’re increasing the risk of fall,” says sleep specialist Timothy Morgenthaler, MD, the Mayo Clinic’s chief patient officer. “Knowledgeable of that, one ought to consider whether there are alternatives or whether the risks outweigh the goal in that setting.”

Dr. Morgenthaler says zolpidem is the most commonly prescribed hypnotic at his hospital, and believes it to be the most common treatment in the U.S. He began studying the issue after nurses reported that it appeared patients were falling after taking the agent. In response to the study, Mayo Clinic removed zolpidem from many of its admission order sets and attempted to help improve patient sleep via other methods, including noise reduction.

“We haven’t removed it from our formulary, and I’m not saying it doesn’t have a role in some points,” he says, “but rather than encouraging it as an option in patients being admitted into the patient, we’re choosing instead now to encourage nonpharmacologic sleep enhancements.” 

Visit our website for more information about HM’s approach to patient falls.

An author of a new study associating the hypnotic zolpidem (Ambien) with higher rates of patient falls says hospitalists should keep the popular drug’s risks front of mind.

The retrospective cohort study in the Journal of Hospital Medicine, “Zolpidem is Independently Associated with Increased Risk of Inpatient Falls,” found that the rate of falls increased nearly six times among patients taking the sleep agent. The research team at the Center for Sleep Medicine at the Mayo Clinic in Rochester, N.Y., calculated one additional fall for every 55 admitted patients who were administered the treatment.

“What this says to me is if one is going to use zolpidem, you have to be aware you’re increasing the risk of fall,” says sleep specialist Timothy Morgenthaler, MD, the Mayo Clinic’s chief patient officer. “Knowledgeable of that, one ought to consider whether there are alternatives or whether the risks outweigh the goal in that setting.”

Dr. Morgenthaler says zolpidem is the most commonly prescribed hypnotic at his hospital, and believes it to be the most common treatment in the U.S. He began studying the issue after nurses reported that it appeared patients were falling after taking the agent. In response to the study, Mayo Clinic removed zolpidem from many of its admission order sets and attempted to help improve patient sleep via other methods, including noise reduction.

“We haven’t removed it from our formulary, and I’m not saying it doesn’t have a role in some points,” he says, “but rather than encouraging it as an option in patients being admitted into the patient, we’re choosing instead now to encourage nonpharmacologic sleep enhancements.” 

Visit our website for more information about HM’s approach to patient falls.

An author of a new study associating the hypnotic zolpidem (Ambien) with higher rates of patient falls says hospitalists should keep the popular drug’s risks front of mind.

The retrospective cohort study in the Journal of Hospital Medicine, “Zolpidem is Independently Associated with Increased Risk of Inpatient Falls,” found that the rate of falls increased nearly six times among patients taking the sleep agent. The research team at the Center for Sleep Medicine at the Mayo Clinic in Rochester, N.Y., calculated one additional fall for every 55 admitted patients who were administered the treatment.

“What this says to me is if one is going to use zolpidem, you have to be aware you’re increasing the risk of fall,” says sleep specialist Timothy Morgenthaler, MD, the Mayo Clinic’s chief patient officer. “Knowledgeable of that, one ought to consider whether there are alternatives or whether the risks outweigh the goal in that setting.”

Dr. Morgenthaler says zolpidem is the most commonly prescribed hypnotic at his hospital, and believes it to be the most common treatment in the U.S. He began studying the issue after nurses reported that it appeared patients were falling after taking the agent. In response to the study, Mayo Clinic removed zolpidem from many of its admission order sets and attempted to help improve patient sleep via other methods, including noise reduction.

“We haven’t removed it from our formulary, and I’m not saying it doesn’t have a role in some points,” he says, “but rather than encouraging it as an option in patients being admitted into the patient, we’re choosing instead now to encourage nonpharmacologic sleep enhancements.” 

Visit our website for more information about HM’s approach to patient falls.

Two recent studies have reached the same surprising conclusion: Adherence to national quality and performance guidelines does not translate into reduced readmissions rates.

Sula Mazimba, MD, MPH, and colleagues at Kettering Medical Center in Kettering, Ohio, focused on congestive heart failure (CHF) patients, documenting compliance with four core CHF performance measures at discharge and subsequent 30-day readmissions. Only one measure-assessment of left ventricular function-had a significant association with readmissions.

A second study published the same month looked at a wider range of diagnoses in a Medicare population at more than 2,000 hospitals nationwide. That study reached similar conclusions about the disconnect between hospitals that followed Hospital Compare process quality measures and their readmission rates.

Dr. Mazimba says hospitalists and other physicians involved in quality improvement (QI) should be more involved in defining quality measures that reflect quality of care for their patients.

“We should be looking for parameters that have a higher yield for outcomes, such as preventing readmissions,” he says, encouraging better symptom management before the CHF patient is hospitalized and enhanced coordination of care after discharge.

Alpesh Amin, MD, MBA, SFHM, professor and chair of the department of medicine and executive director of the hospitalist program at the University of California at Irvine, says the findings are important, but he adds that the core quality measures studied were never designed to address readmissions.

“The challenge is to find a way to connect the dots between the core measures and readmissions,” he says.

Learn more about the four "core" heart failure quality measures for hospitals by visiting the Resource Rooms on the SHM website, or check out this 80-page implementation guide, “Improving Heart Failure Care for Hospitalized Patients [PDF],” also available on SHM’s website.

Read The Hospitalist columnist Win Whitcomb’s take on readmissions penalty programs.

Two recent studies have reached the same surprising conclusion: Adherence to national quality and performance guidelines does not translate into reduced readmissions rates.

Sula Mazimba, MD, MPH, and colleagues at Kettering Medical Center in Kettering, Ohio, focused on congestive heart failure (CHF) patients, documenting compliance with four core CHF performance measures at discharge and subsequent 30-day readmissions. Only one measure-assessment of left ventricular function-had a significant association with readmissions.

A second study published the same month looked at a wider range of diagnoses in a Medicare population at more than 2,000 hospitals nationwide. That study reached similar conclusions about the disconnect between hospitals that followed Hospital Compare process quality measures and their readmission rates.

Dr. Mazimba says hospitalists and other physicians involved in quality improvement (QI) should be more involved in defining quality measures that reflect quality of care for their patients.

“We should be looking for parameters that have a higher yield for outcomes, such as preventing readmissions,” he says, encouraging better symptom management before the CHF patient is hospitalized and enhanced coordination of care after discharge.

Alpesh Amin, MD, MBA, SFHM, professor and chair of the department of medicine and executive director of the hospitalist program at the University of California at Irvine, says the findings are important, but he adds that the core quality measures studied were never designed to address readmissions.

“The challenge is to find a way to connect the dots between the core measures and readmissions,” he says.

Learn more about the four "core" heart failure quality measures for hospitals by visiting the Resource Rooms on the SHM website, or check out this 80-page implementation guide, “Improving Heart Failure Care for Hospitalized Patients [PDF],” also available on SHM’s website.

Read The Hospitalist columnist Win Whitcomb’s take on readmissions penalty programs.

Two recent studies have reached the same surprising conclusion: Adherence to national quality and performance guidelines does not translate into reduced readmissions rates.

Sula Mazimba, MD, MPH, and colleagues at Kettering Medical Center in Kettering, Ohio, focused on congestive heart failure (CHF) patients, documenting compliance with four core CHF performance measures at discharge and subsequent 30-day readmissions. Only one measure-assessment of left ventricular function-had a significant association with readmissions.

A second study published the same month looked at a wider range of diagnoses in a Medicare population at more than 2,000 hospitals nationwide. That study reached similar conclusions about the disconnect between hospitals that followed Hospital Compare process quality measures and their readmission rates.

Dr. Mazimba says hospitalists and other physicians involved in quality improvement (QI) should be more involved in defining quality measures that reflect quality of care for their patients.

“We should be looking for parameters that have a higher yield for outcomes, such as preventing readmissions,” he says, encouraging better symptom management before the CHF patient is hospitalized and enhanced coordination of care after discharge.

Alpesh Amin, MD, MBA, SFHM, professor and chair of the department of medicine and executive director of the hospitalist program at the University of California at Irvine, says the findings are important, but he adds that the core quality measures studied were never designed to address readmissions.

“The challenge is to find a way to connect the dots between the core measures and readmissions,” he says.

Learn more about the four "core" heart failure quality measures for hospitals by visiting the Resource Rooms on the SHM website, or check out this 80-page implementation guide, “Improving Heart Failure Care for Hospitalized Patients [PDF],” also available on SHM’s website.

Read The Hospitalist columnist Win Whitcomb’s take on readmissions penalty programs.

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.

BOSTON  – In patients who had chronic hepatitis B infections and documented lamivudine resistance, tenofovir with or without emtricitabine produced high rates of viral suppression with no detectable resistance over 2 years.

In a phase IIIb randomized study, 89% of lamivudine-resistant patients with HBV who were randomly assigned to receive tenofovir (Viread) alone met the primary end point of HBV DNA below 400 copies/mL, compared with 86% of those assigned to a tenofovir/emtricitabine (Emtriva) combination, in an intention-to-treat analysis, Dr. Scott Fung, assistant professor of hepatology at the University of Toronto, reported at the annual meeting of the American Association for the Study of Liver Diseases.

©CDC/ Dr. Erskine Palmer

"Tenofovir monotherapy was just as safe and effective as combination therapy, suggesting that monotherapy alone was sufficient for treatment of hepatitis B," Dr. Fung said.

In addition to the high rate of viral resistance, tenofovir was associated with normalization of ALT levels in a majority of patients, and with no emergent viral resistance, he said.

The investigators enrolled 280 patients who carried virus with lamivudine-resistant mutations, were viremic (HBV DNA greater than 10³/IU per mL), and were still on lamivudine until the day of randomization. Current or prior treatment with adefovir (Hepsera) was allowed as long as the patient had received less than 48 total weeks of therapy.

A total of 133 patients who were assigned to receive tenofovir 300 mg daily completed 96 weeks of treatment and were thus available for analysis, as were 125 of those assigned to emtricitabine/tenofovir in a fixed-dose combination.

As noted before, the rates of HBV DNA below 400 copies/mL were 89% for the monotherapy arm and 86% for the combination in an analysis that considered missing data as treatment failure. When missing data were excluded from an on-treatment analysis, however, the respective rates were 96% and 95%.

Using a lower cutoff point, less than 169 copies/mL, the respective rates at 96 weeks were 86% and 84%.

In all, 70% of patients in each group had normal ALT levels at 96 weeks, and among patients with abnormally high levels at baseline nearly two-thirds in each group had normalization of ALT during the study.

The HBV e-antigen loss rate was modest, at 15% of patients on tenofovir alone and 13% on the combination. HBeAg seroconversion occurred in 11% and 10%, respectively.

Among 18 patients who qualified for genotypic resistance testing at their last on-treatment visit, there were no viral isolates demonstrating tenofovir resistance, Dr. Fung said.

There were three deaths during the study: one from gastrointestinal hemorrhage in a patient in the monotherapy group and two – one from cardiac arrest and sepsis in a patient with hepatocellular carcinoma and one from bronchopneumonia – in the combination group. The deaths were judged to be unrelated to study treatment.

There was only one serious treatment-related adverse event, occurring in the combination group (the event was unspecified), and only three patients discontinued because of adverse events – one in the monotherapy arm and two in the combination group. Five patients on tenofovir alone and four on the combination had creatinine clearance less than 50 mL/min at study end; these patients all had low baseline creatinine clearance levels, ranging from 41 to 69 mL/min, Dr. Fung noted.

The authors also looked at bone mineral density levels at baseline and at study end in 239 patients for who dual-energy x-ray absorptiometry data were available. At baseline, 33% of patients were determined to have osteopenia and 7% to have osteoporosis on spine scans and 22% and 1.3%, respectively, on hip scans. Repeat scans at 96 weeks showed that the majority of patients had a reduction in bone mineral density of about 22%, a decline that was considered not clinically significant, he said.

The study was funded by Gilead Sciences. Dr. Fung disclosed receiving grant/research support and speaking/teaching fees from the company.

BOSTON  – In patients who had chronic hepatitis B infections and documented lamivudine resistance, tenofovir with or without emtricitabine produced high rates of viral suppression with no detectable resistance over 2 years.

In a phase IIIb randomized study, 89% of lamivudine-resistant patients with HBV who were randomly assigned to receive tenofovir (Viread) alone met the primary end point of HBV DNA below 400 copies/mL, compared with 86% of those assigned to a tenofovir/emtricitabine (Emtriva) combination, in an intention-to-treat analysis, Dr. Scott Fung, assistant professor of hepatology at the University of Toronto, reported at the annual meeting of the American Association for the Study of Liver Diseases.

©CDC/ Dr. Erskine Palmer

"Tenofovir monotherapy was just as safe and effective as combination therapy, suggesting that monotherapy alone was sufficient for treatment of hepatitis B," Dr. Fung said.

In addition to the high rate of viral resistance, tenofovir was associated with normalization of ALT levels in a majority of patients, and with no emergent viral resistance, he said.

The investigators enrolled 280 patients who carried virus with lamivudine-resistant mutations, were viremic (HBV DNA greater than 10³/IU per mL), and were still on lamivudine until the day of randomization. Current or prior treatment with adefovir (Hepsera) was allowed as long as the patient had received less than 48 total weeks of therapy.

A total of 133 patients who were assigned to receive tenofovir 300 mg daily completed 96 weeks of treatment and were thus available for analysis, as were 125 of those assigned to emtricitabine/tenofovir in a fixed-dose combination.

As noted before, the rates of HBV DNA below 400 copies/mL were 89% for the monotherapy arm and 86% for the combination in an analysis that considered missing data as treatment failure. When missing data were excluded from an on-treatment analysis, however, the respective rates were 96% and 95%.

Using a lower cutoff point, less than 169 copies/mL, the respective rates at 96 weeks were 86% and 84%.

In all, 70% of patients in each group had normal ALT levels at 96 weeks, and among patients with abnormally high levels at baseline nearly two-thirds in each group had normalization of ALT during the study.

The HBV e-antigen loss rate was modest, at 15% of patients on tenofovir alone and 13% on the combination. HBeAg seroconversion occurred in 11% and 10%, respectively.

Among 18 patients who qualified for genotypic resistance testing at their last on-treatment visit, there were no viral isolates demonstrating tenofovir resistance, Dr. Fung said.

There were three deaths during the study: one from gastrointestinal hemorrhage in a patient in the monotherapy group and two – one from cardiac arrest and sepsis in a patient with hepatocellular carcinoma and one from bronchopneumonia – in the combination group. The deaths were judged to be unrelated to study treatment.

There was only one serious treatment-related adverse event, occurring in the combination group (the event was unspecified), and only three patients discontinued because of adverse events – one in the monotherapy arm and two in the combination group. Five patients on tenofovir alone and four on the combination had creatinine clearance less than 50 mL/min at study end; these patients all had low baseline creatinine clearance levels, ranging from 41 to 69 mL/min, Dr. Fung noted.

The authors also looked at bone mineral density levels at baseline and at study end in 239 patients for who dual-energy x-ray absorptiometry data were available. At baseline, 33% of patients were determined to have osteopenia and 7% to have osteoporosis on spine scans and 22% and 1.3%, respectively, on hip scans. Repeat scans at 96 weeks showed that the majority of patients had a reduction in bone mineral density of about 22%, a decline that was considered not clinically significant, he said.

The study was funded by Gilead Sciences. Dr. Fung disclosed receiving grant/research support and speaking/teaching fees from the company.

BOSTON  – In patients who had chronic hepatitis B infections and documented lamivudine resistance, tenofovir with or without emtricitabine produced high rates of viral suppression with no detectable resistance over 2 years.

In a phase IIIb randomized study, 89% of lamivudine-resistant patients with HBV who were randomly assigned to receive tenofovir (Viread) alone met the primary end point of HBV DNA below 400 copies/mL, compared with 86% of those assigned to a tenofovir/emtricitabine (Emtriva) combination, in an intention-to-treat analysis, Dr. Scott Fung, assistant professor of hepatology at the University of Toronto, reported at the annual meeting of the American Association for the Study of Liver Diseases.

©CDC/ Dr. Erskine Palmer

"Tenofovir monotherapy was just as safe and effective as combination therapy, suggesting that monotherapy alone was sufficient for treatment of hepatitis B," Dr. Fung said.

In addition to the high rate of viral resistance, tenofovir was associated with normalization of ALT levels in a majority of patients, and with no emergent viral resistance, he said.

The investigators enrolled 280 patients who carried virus with lamivudine-resistant mutations, were viremic (HBV DNA greater than 10³/IU per mL), and were still on lamivudine until the day of randomization. Current or prior treatment with adefovir (Hepsera) was allowed as long as the patient had received less than 48 total weeks of therapy.

A total of 133 patients who were assigned to receive tenofovir 300 mg daily completed 96 weeks of treatment and were thus available for analysis, as were 125 of those assigned to emtricitabine/tenofovir in a fixed-dose combination.

As noted before, the rates of HBV DNA below 400 copies/mL were 89% for the monotherapy arm and 86% for the combination in an analysis that considered missing data as treatment failure. When missing data were excluded from an on-treatment analysis, however, the respective rates were 96% and 95%.

Using a lower cutoff point, less than 169 copies/mL, the respective rates at 96 weeks were 86% and 84%.

In all, 70% of patients in each group had normal ALT levels at 96 weeks, and among patients with abnormally high levels at baseline nearly two-thirds in each group had normalization of ALT during the study.

The HBV e-antigen loss rate was modest, at 15% of patients on tenofovir alone and 13% on the combination. HBeAg seroconversion occurred in 11% and 10%, respectively.

Among 18 patients who qualified for genotypic resistance testing at their last on-treatment visit, there were no viral isolates demonstrating tenofovir resistance, Dr. Fung said.

There were three deaths during the study: one from gastrointestinal hemorrhage in a patient in the monotherapy group and two – one from cardiac arrest and sepsis in a patient with hepatocellular carcinoma and one from bronchopneumonia – in the combination group. The deaths were judged to be unrelated to study treatment.

There was only one serious treatment-related adverse event, occurring in the combination group (the event was unspecified), and only three patients discontinued because of adverse events – one in the monotherapy arm and two in the combination group. Five patients on tenofovir alone and four on the combination had creatinine clearance less than 50 mL/min at study end; these patients all had low baseline creatinine clearance levels, ranging from 41 to 69 mL/min, Dr. Fung noted.

The authors also looked at bone mineral density levels at baseline and at study end in 239 patients for who dual-energy x-ray absorptiometry data were available. At baseline, 33% of patients were determined to have osteopenia and 7% to have osteoporosis on spine scans and 22% and 1.3%, respectively, on hip scans. Repeat scans at 96 weeks showed that the majority of patients had a reduction in bone mineral density of about 22%, a decline that was considered not clinically significant, he said.

The study was funded by Gilead Sciences. Dr. Fung disclosed receiving grant/research support and speaking/teaching fees from the company.

BOSTON – Patients with HIV and hepatitis C coinfection had high levels of sustained viral response with regimens combining select antiretroviral agents with telaprevir, pegylated interferon, and ribavirin, said investigators at the annual meeting of the American Association for the Study of Liver Diseases.

The key to avoiding adverse drug interactions between telaprevir (Incivek) and highly active antiretroviral therapy (HAART) regimens is careful selection of HIV therapy, said Dr. Mark Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University in Baltimore.

Dr. Sulkowski and his colleagues showed in a randomized phase III study that a combination of specific antiretroviral agents with telaprevir and pegylated interferon alfa-2a (PEG-IFN) and ribavirin (RBV) was associated with a 74% SVR₂₄ rate, compared with HAART and PEG-IFN only.

"Overall, 74% of patients treated with telaprevir in combination with peg-interferon and ribavirin achieved SVR [sustained virological response], compared to 45% of those treated with placebo. Drug interactions with telaprevir and selected antiretroviral therapies, specifically atazanavir/ritonavir and efavirenz, were not clinically meaningful," Dr. Sulkowski said.

A separate study by European investigators showed that the likelihood that patients with HIV/HCV coinfection will clear HCV from serum may depend on the presence of ribavirin in a regimen, and on HCV genotype.

"Ribavirin is important in the management of acute hepatitis C in HIV-positive patients. Almost all patients with genotype 2 and 3 infections were able to clear virus with combination therapy [PEG-IFN and RBV]," said lead investigator Dr. Christoph Boesecke of the University of Bonn, Germany.

Safety Concerns

Some infectious disease specialists have expressed concern that the addition of a direct-acting antiviral agent in combination with PEG-IFN/RBV could compromise the efficacy and/or safety of a HAART regimen.

To test the HAART/direct-acting antiviral agent combination, Dr. Sulkowski and his colleagues enrolled patients with HIV/HCV coinfection in a two-part study. In part A, patients were assigned on a 1:1 ratio to receive either telaprevir or placebo, each with PEG-IFN/RBV.

In part B, patients on a HAART regimen (either a combination of efavirenz, tenofovir, and emtricitabine or ritonavir-boosted atazanavir, tenofovir, and emtricitabine or lamivudine) were assigned on a 2:1 basis to receive telaprevir or placebo plus PEG-IFN/RBV. All patients were treated for 48 weeks, with an additional 24 weeks of follow-up.

HCV RNA levels on study were measured at various time points, and the investigators looked for drug interactions, adverse events, viral breakthrough, and other clinical measures.

At 24 weeks post treatment, the HCV sustained virologic response rate (SVR₂₄) among patients treated with telaprevir and PEG-IFN/RBV but not an antiretroviral therapy was 71%, compared with 33% among those treated with placebo and PEG-IFN/RBV.

Among patients on the HAART regimen containing efavirenz plus telaprevir and PEG-IFN/RBV, 69% had an SVR₂₄, compared with 38% of those who received the same HAART regimen without telaprevir. Among those on the atazanavir-containing regimen, 73% had an SVR₂₄, compared with 50% of controls who received only PEG-IFN/RBV plus HAART.

The serum concentrations of both atazanavir and efavirenz were similar whether the patients had received telaprevir or not, and there were no cases of HIV viral breakthrough, although CD4 cell counts decreased among patients taking PEG-IFN/RBV and either telaprevir or placebo. Nonetheless, investigators did not see HIV-related adverse events, Dr. Sulkowski said.

Patients on efavirenz did require a telaprevir dose increase, but the required increase was adequate for maintaining exposure to the direct-acting antiviral agent, he added.

Genotype Matters

Dr. Boesecke and his colleagues in the European AIDS Treatment Network looked at the effect of HCV genotype and ribavirin on SVR rates in the treatment of coinfected patients. They reported on 303 HIV-infected men from the Austria, France, Germany, and the United Kingdom who had been diagnosed with acute HCV infections. Of this group, 273 were treated with PEG-IFN/RBV, and 30 were treated with PEG-IFN alone. In all, 88% of the patients who received ribavirin had weight-based doses (1,000 mg for those 75 kg and under, and 1,200 mg for those over 75 kg).

A majority of the patients (69%) were infected with genotype 1; 4% had genotype 2; 11% had genotype 3; and 16% had genotype 4 infections. About one-third of patients had 24 weeks of therapy, and the remaining third had 48 weeks. Median time from HCV diagnosis to the start of treatment was about 10 weeks.

Among all patients, 52% of those received PEG-IFN alone, and 52% of those who also received ribavirin had a rapid virologic response (RVR), defined as HCV RNA negative at 4 weeks. Respective SVR₂₄ rates were 66.7% and 69.6%.

When the investigators broke it out by genotype, however, they found that while the addition of ribavirin did not significantly change either RVR or SVR₂₄ rates among patients with genotype 1 or 3 infections, 60% of patients with genotype 2 or 3 infections on PEG-IFN monotherapy had a 60% SVR^24,, whereas those on PEG-IFN/RBV had a 94% SVR₂₄. indicating a significant benefit to adding RBV (P = .016). The RVR rates were not significantly different in these patients, however.

There were no significant differences in either the total number or severity of adverse events among the various genotypes. In 10% of all cases a ribavirin dose reduction was required, and interferon dose reductions were required in 6% of cases.

Toxicities required stopping HCV therapy in 17 patients (6%).

"We saw high sustained virologic response rates if you treat hepatitis C early on, when it’s still acute, compared to when the disease is left to a chronic course in HIV patients," said Dr. Boesecke

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. Boesecke’s study was supported by the European AIDS Treatment Network. He reported no conflict of interest.

BOSTON – Patients with HIV and hepatitis C coinfection had high levels of sustained viral response with regimens combining select antiretroviral agents with telaprevir, pegylated interferon, and ribavirin, said investigators at the annual meeting of the American Association for the Study of Liver Diseases.

The key to avoiding adverse drug interactions between telaprevir (Incivek) and highly active antiretroviral therapy (HAART) regimens is careful selection of HIV therapy, said Dr. Mark Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University in Baltimore.

Dr. Sulkowski and his colleagues showed in a randomized phase III study that a combination of specific antiretroviral agents with telaprevir and pegylated interferon alfa-2a (PEG-IFN) and ribavirin (RBV) was associated with a 74% SVR₂₄ rate, compared with HAART and PEG-IFN only.

"Overall, 74% of patients treated with telaprevir in combination with peg-interferon and ribavirin achieved SVR [sustained virological response], compared to 45% of those treated with placebo. Drug interactions with telaprevir and selected antiretroviral therapies, specifically atazanavir/ritonavir and efavirenz, were not clinically meaningful," Dr. Sulkowski said.

A separate study by European investigators showed that the likelihood that patients with HIV/HCV coinfection will clear HCV from serum may depend on the presence of ribavirin in a regimen, and on HCV genotype.

"Ribavirin is important in the management of acute hepatitis C in HIV-positive patients. Almost all patients with genotype 2 and 3 infections were able to clear virus with combination therapy [PEG-IFN and RBV]," said lead investigator Dr. Christoph Boesecke of the University of Bonn, Germany.

Safety Concerns

Some infectious disease specialists have expressed concern that the addition of a direct-acting antiviral agent in combination with PEG-IFN/RBV could compromise the efficacy and/or safety of a HAART regimen.

To test the HAART/direct-acting antiviral agent combination, Dr. Sulkowski and his colleagues enrolled patients with HIV/HCV coinfection in a two-part study. In part A, patients were assigned on a 1:1 ratio to receive either telaprevir or placebo, each with PEG-IFN/RBV.

In part B, patients on a HAART regimen (either a combination of efavirenz, tenofovir, and emtricitabine or ritonavir-boosted atazanavir, tenofovir, and emtricitabine or lamivudine) were assigned on a 2:1 basis to receive telaprevir or placebo plus PEG-IFN/RBV. All patients were treated for 48 weeks, with an additional 24 weeks of follow-up.

HCV RNA levels on study were measured at various time points, and the investigators looked for drug interactions, adverse events, viral breakthrough, and other clinical measures.

At 24 weeks post treatment, the HCV sustained virologic response rate (SVR₂₄) among patients treated with telaprevir and PEG-IFN/RBV but not an antiretroviral therapy was 71%, compared with 33% among those treated with placebo and PEG-IFN/RBV.

Among patients on the HAART regimen containing efavirenz plus telaprevir and PEG-IFN/RBV, 69% had an SVR₂₄, compared with 38% of those who received the same HAART regimen without telaprevir. Among those on the atazanavir-containing regimen, 73% had an SVR₂₄, compared with 50% of controls who received only PEG-IFN/RBV plus HAART.

The serum concentrations of both atazanavir and efavirenz were similar whether the patients had received telaprevir or not, and there were no cases of HIV viral breakthrough, although CD4 cell counts decreased among patients taking PEG-IFN/RBV and either telaprevir or placebo. Nonetheless, investigators did not see HIV-related adverse events, Dr. Sulkowski said.

Patients on efavirenz did require a telaprevir dose increase, but the required increase was adequate for maintaining exposure to the direct-acting antiviral agent, he added.

Genotype Matters

Dr. Boesecke and his colleagues in the European AIDS Treatment Network looked at the effect of HCV genotype and ribavirin on SVR rates in the treatment of coinfected patients. They reported on 303 HIV-infected men from the Austria, France, Germany, and the United Kingdom who had been diagnosed with acute HCV infections. Of this group, 273 were treated with PEG-IFN/RBV, and 30 were treated with PEG-IFN alone. In all, 88% of the patients who received ribavirin had weight-based doses (1,000 mg for those 75 kg and under, and 1,200 mg for those over 75 kg).

A majority of the patients (69%) were infected with genotype 1; 4% had genotype 2; 11% had genotype 3; and 16% had genotype 4 infections. About one-third of patients had 24 weeks of therapy, and the remaining third had 48 weeks. Median time from HCV diagnosis to the start of treatment was about 10 weeks.

Among all patients, 52% of those received PEG-IFN alone, and 52% of those who also received ribavirin had a rapid virologic response (RVR), defined as HCV RNA negative at 4 weeks. Respective SVR₂₄ rates were 66.7% and 69.6%.

When the investigators broke it out by genotype, however, they found that while the addition of ribavirin did not significantly change either RVR or SVR₂₄ rates among patients with genotype 1 or 3 infections, 60% of patients with genotype 2 or 3 infections on PEG-IFN monotherapy had a 60% SVR^24,, whereas those on PEG-IFN/RBV had a 94% SVR₂₄. indicating a significant benefit to adding RBV (P = .016). The RVR rates were not significantly different in these patients, however.

There were no significant differences in either the total number or severity of adverse events among the various genotypes. In 10% of all cases a ribavirin dose reduction was required, and interferon dose reductions were required in 6% of cases.

Toxicities required stopping HCV therapy in 17 patients (6%).

"We saw high sustained virologic response rates if you treat hepatitis C early on, when it’s still acute, compared to when the disease is left to a chronic course in HIV patients," said Dr. Boesecke

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. Boesecke’s study was supported by the European AIDS Treatment Network. He reported no conflict of interest.

BOSTON – Patients with HIV and hepatitis C coinfection had high levels of sustained viral response with regimens combining select antiretroviral agents with telaprevir, pegylated interferon, and ribavirin, said investigators at the annual meeting of the American Association for the Study of Liver Diseases.

The key to avoiding adverse drug interactions between telaprevir (Incivek) and highly active antiretroviral therapy (HAART) regimens is careful selection of HIV therapy, said Dr. Mark Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University in Baltimore.

Dr. Sulkowski and his colleagues showed in a randomized phase III study that a combination of specific antiretroviral agents with telaprevir and pegylated interferon alfa-2a (PEG-IFN) and ribavirin (RBV) was associated with a 74% SVR₂₄ rate, compared with HAART and PEG-IFN only.

"Overall, 74% of patients treated with telaprevir in combination with peg-interferon and ribavirin achieved SVR [sustained virological response], compared to 45% of those treated with placebo. Drug interactions with telaprevir and selected antiretroviral therapies, specifically atazanavir/ritonavir and efavirenz, were not clinically meaningful," Dr. Sulkowski said.

A separate study by European investigators showed that the likelihood that patients with HIV/HCV coinfection will clear HCV from serum may depend on the presence of ribavirin in a regimen, and on HCV genotype.

"Ribavirin is important in the management of acute hepatitis C in HIV-positive patients. Almost all patients with genotype 2 and 3 infections were able to clear virus with combination therapy [PEG-IFN and RBV]," said lead investigator Dr. Christoph Boesecke of the University of Bonn, Germany.

Safety Concerns

Some infectious disease specialists have expressed concern that the addition of a direct-acting antiviral agent in combination with PEG-IFN/RBV could compromise the efficacy and/or safety of a HAART regimen.

To test the HAART/direct-acting antiviral agent combination, Dr. Sulkowski and his colleagues enrolled patients with HIV/HCV coinfection in a two-part study. In part A, patients were assigned on a 1:1 ratio to receive either telaprevir or placebo, each with PEG-IFN/RBV.

In part B, patients on a HAART regimen (either a combination of efavirenz, tenofovir, and emtricitabine or ritonavir-boosted atazanavir, tenofovir, and emtricitabine or lamivudine) were assigned on a 2:1 basis to receive telaprevir or placebo plus PEG-IFN/RBV. All patients were treated for 48 weeks, with an additional 24 weeks of follow-up.

HCV RNA levels on study were measured at various time points, and the investigators looked for drug interactions, adverse events, viral breakthrough, and other clinical measures.

At 24 weeks post treatment, the HCV sustained virologic response rate (SVR₂₄) among patients treated with telaprevir and PEG-IFN/RBV but not an antiretroviral therapy was 71%, compared with 33% among those treated with placebo and PEG-IFN/RBV.

Among patients on the HAART regimen containing efavirenz plus telaprevir and PEG-IFN/RBV, 69% had an SVR₂₄, compared with 38% of those who received the same HAART regimen without telaprevir. Among those on the atazanavir-containing regimen, 73% had an SVR₂₄, compared with 50% of controls who received only PEG-IFN/RBV plus HAART.

The serum concentrations of both atazanavir and efavirenz were similar whether the patients had received telaprevir or not, and there were no cases of HIV viral breakthrough, although CD4 cell counts decreased among patients taking PEG-IFN/RBV and either telaprevir or placebo. Nonetheless, investigators did not see HIV-related adverse events, Dr. Sulkowski said.

Patients on efavirenz did require a telaprevir dose increase, but the required increase was adequate for maintaining exposure to the direct-acting antiviral agent, he added.

Genotype Matters

Dr. Boesecke and his colleagues in the European AIDS Treatment Network looked at the effect of HCV genotype and ribavirin on SVR rates in the treatment of coinfected patients. They reported on 303 HIV-infected men from the Austria, France, Germany, and the United Kingdom who had been diagnosed with acute HCV infections. Of this group, 273 were treated with PEG-IFN/RBV, and 30 were treated with PEG-IFN alone. In all, 88% of the patients who received ribavirin had weight-based doses (1,000 mg for those 75 kg and under, and 1,200 mg for those over 75 kg).

A majority of the patients (69%) were infected with genotype 1; 4% had genotype 2; 11% had genotype 3; and 16% had genotype 4 infections. About one-third of patients had 24 weeks of therapy, and the remaining third had 48 weeks. Median time from HCV diagnosis to the start of treatment was about 10 weeks.

Among all patients, 52% of those received PEG-IFN alone, and 52% of those who also received ribavirin had a rapid virologic response (RVR), defined as HCV RNA negative at 4 weeks. Respective SVR₂₄ rates were 66.7% and 69.6%.

When the investigators broke it out by genotype, however, they found that while the addition of ribavirin did not significantly change either RVR or SVR₂₄ rates among patients with genotype 1 or 3 infections, 60% of patients with genotype 2 or 3 infections on PEG-IFN monotherapy had a 60% SVR^24,, whereas those on PEG-IFN/RBV had a 94% SVR₂₄. indicating a significant benefit to adding RBV (P = .016). The RVR rates were not significantly different in these patients, however.

There were no significant differences in either the total number or severity of adverse events among the various genotypes. In 10% of all cases a ribavirin dose reduction was required, and interferon dose reductions were required in 6% of cases.

Toxicities required stopping HCV therapy in 17 patients (6%).

"We saw high sustained virologic response rates if you treat hepatitis C early on, when it’s still acute, compared to when the disease is left to a chronic course in HIV patients," said Dr. Boesecke

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. Boesecke’s study was supported by the European AIDS Treatment Network. He reported no conflict of interest.

BOSTON – In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial looking at the safety of the regimen.

Although the efficacy of direct-acting antiviral regimens involving the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) combined with pegylated interferon alfa-2a or -2b in combination with ribavirin (PEG-IFN/RBV) in cirrhotic nonresponders to prior therapy was good , their safety was "poor," according to Dr. Christophe Hézode of the Hôpital Henri Mondor in Créteil, France.

Virologic response at 16 weeks in a per-protocol analysis was associated with a virologic response rate of 92% with telaprevir and 77% with boceprevir.

However, there were increased rates of serious adverse events and more difficult-to-manage anemia than in phase III trials for telaprevir and boceprevir, which included only a few patients with cirrhosis, Dr. Hézode said at the annual meeting of the American Association for the Study of Liver Diseases.

In treatment-experienced cirrhotic patients with platelet counts of 100,000/mm³ or serum albumin levels below 35 g/L, clinicians should weigh the risks and benefits of such regimens, with patients treated on a case-by-case basis because of the high risk for severe complications, Dr. Hézode said.

"However, cirrhotic experienced patients without predictors of severe complications clearly should be treated, but cautiously and carefully monitored," he added.

Dr. Hézode and his coinvestigators in the French Cohort of Therapeutic Failure and Resistances in Patients Treated With a Protease Inhibitor (telaprevir or boceprevir), Pegylated Interferon, and Ribavirin (CUPIC) trial studied two cohorts of patients with chronic hepatitis C virus (HCV) infections, and compensated cirrhosis (Child Pugh class A) who had either relapsed or had only a partial response to prior therapy, with partial response defined as at least a 2 log₁₀ decline inV RNA but failure to clear virus by week 24.

He presented data on 497 patients who had completed 16 weeks of therapy on one of two regimens. In one cohort, 292 patients received 12 weeks of telaprevir 750 mg every 8 hours, and PEG-IFN alfa-2a (Pegasys) 180 mcg/wk with ribavirin 1,000-1,200 mg/day, followed by PEG-IFN/RBV through 48 weeks. In the second cohort, patients received a 4-week initiation phase with PEG-IFN alfa-2b (PegIntron) and ribavirin, followed by 44 weeks of boceprevir 800 mg every 8 hours, PEG-IFN 1.5 mcg/kg per wk, and ribavirin 800-1,400 mg/day.

At week 16, 45% of patients on telaprevir had had at least one serious adverse event, with 14.7% terminating therapy because of a serious side effect. In all, nearly one-fourth (22.6%) discontinued therapy, and there were five deaths: from septicemia, septic shock, pneumopathy, endocarditis, and bleeding esophageal varices. Other complications in this group included grade 3 or 4 infections in 6.5%, grade 3 or 4 hepatic decompensation in 2%, grade 3/4 asthenia in 5.5%, and renal failure in 1.7%.

Hematologic adverse events included anemia of grade 2 or greater in 30.4%, erythropoietin use in 53.8%, blood transfusion in 16.1%, and ribavirin dose reduction in 13%. In addition, 2.7% of patients had grade 3 or 4 neutropenia, and 1.7% had grade 3 or 4 thrombocytopenia.

In the boceprevir group, 32.7% had at least one serious adverse event, 26.3% discontinued prematurely, and 7.3% discontinued because of serious events. The cause of one death was described as pneumopathy. Grade 3/4 adverse events involved infections in 2.4%, hepatic decompensation in 2.9%, and asthenia in 5.8%. There were no cases of renal failure in this group.

Hematologic events in patients on boceprevir included grade 2 or greater anemia in 27.8%, erythropoietin use in 46.3%, blood transfusion in 6.3%, and ribavirin dose reduction in 10.7%.

Grade 3/4 neutropenia was seen in 4.4%, and grade 3/4 thrombocytopenia in 5.4%. Two patients (1%) in this cohort received thrombopoietin.

In a multivariate analysis, significant baseline predictors of severe complications (death, severe infection, and hepatic decompensation) included platelet counts of 100,000/mm³ or lower (odds ratio, 3.11; P = .0098) and a serum albumin level below 35 g/L (OR, 6.33; P less than .0001).

Baseline predictors for severe anemia (hemoglobin less than 8 g/dL) or blood transfusion included female gender (OR, 2.19; P = .023), no lead-in phase (OR, 2.25; P = .018), age 65 years or older (OR, 3.04; P = .0014), and hemoglobin 12 g/dL or lower for women and 13 g/dL or lower for men (OR, 5.30; P less than .0001),

The study was sponsored by ANRS, the French National Agency for Research in AIDS and Viral Hepatitis, with support from INSERM, the French National Institute for Health and Medical Research. Dr. Hézode said that he has no financial conflicts of interest, but disclosed serving as a speaker and adviser for Abbott, BMS, Gilead, Janssen, Merck, and Roche.

BOSTON – In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial looking at the safety of the regimen.

Although the efficacy of direct-acting antiviral regimens involving the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) combined with pegylated interferon alfa-2a or -2b in combination with ribavirin (PEG-IFN/RBV) in cirrhotic nonresponders to prior therapy was good , their safety was "poor," according to Dr. Christophe Hézode of the Hôpital Henri Mondor in Créteil, France.

Virologic response at 16 weeks in a per-protocol analysis was associated with a virologic response rate of 92% with telaprevir and 77% with boceprevir.

However, there were increased rates of serious adverse events and more difficult-to-manage anemia than in phase III trials for telaprevir and boceprevir, which included only a few patients with cirrhosis, Dr. Hézode said at the annual meeting of the American Association for the Study of Liver Diseases.

In treatment-experienced cirrhotic patients with platelet counts of 100,000/mm³ or serum albumin levels below 35 g/L, clinicians should weigh the risks and benefits of such regimens, with patients treated on a case-by-case basis because of the high risk for severe complications, Dr. Hézode said.

"However, cirrhotic experienced patients without predictors of severe complications clearly should be treated, but cautiously and carefully monitored," he added.

Dr. Hézode and his coinvestigators in the French Cohort of Therapeutic Failure and Resistances in Patients Treated With a Protease Inhibitor (telaprevir or boceprevir), Pegylated Interferon, and Ribavirin (CUPIC) trial studied two cohorts of patients with chronic hepatitis C virus (HCV) infections, and compensated cirrhosis (Child Pugh class A) who had either relapsed or had only a partial response to prior therapy, with partial response defined as at least a 2 log₁₀ decline inV RNA but failure to clear virus by week 24.

He presented data on 497 patients who had completed 16 weeks of therapy on one of two regimens. In one cohort, 292 patients received 12 weeks of telaprevir 750 mg every 8 hours, and PEG-IFN alfa-2a (Pegasys) 180 mcg/wk with ribavirin 1,000-1,200 mg/day, followed by PEG-IFN/RBV through 48 weeks. In the second cohort, patients received a 4-week initiation phase with PEG-IFN alfa-2b (PegIntron) and ribavirin, followed by 44 weeks of boceprevir 800 mg every 8 hours, PEG-IFN 1.5 mcg/kg per wk, and ribavirin 800-1,400 mg/day.

At week 16, 45% of patients on telaprevir had had at least one serious adverse event, with 14.7% terminating therapy because of a serious side effect. In all, nearly one-fourth (22.6%) discontinued therapy, and there were five deaths: from septicemia, septic shock, pneumopathy, endocarditis, and bleeding esophageal varices. Other complications in this group included grade 3 or 4 infections in 6.5%, grade 3 or 4 hepatic decompensation in 2%, grade 3/4 asthenia in 5.5%, and renal failure in 1.7%.

Hematologic adverse events included anemia of grade 2 or greater in 30.4%, erythropoietin use in 53.8%, blood transfusion in 16.1%, and ribavirin dose reduction in 13%. In addition, 2.7% of patients had grade 3 or 4 neutropenia, and 1.7% had grade 3 or 4 thrombocytopenia.

In the boceprevir group, 32.7% had at least one serious adverse event, 26.3% discontinued prematurely, and 7.3% discontinued because of serious events. The cause of one death was described as pneumopathy. Grade 3/4 adverse events involved infections in 2.4%, hepatic decompensation in 2.9%, and asthenia in 5.8%. There were no cases of renal failure in this group.

Hematologic events in patients on boceprevir included grade 2 or greater anemia in 27.8%, erythropoietin use in 46.3%, blood transfusion in 6.3%, and ribavirin dose reduction in 10.7%.

Grade 3/4 neutropenia was seen in 4.4%, and grade 3/4 thrombocytopenia in 5.4%. Two patients (1%) in this cohort received thrombopoietin.

In a multivariate analysis, significant baseline predictors of severe complications (death, severe infection, and hepatic decompensation) included platelet counts of 100,000/mm³ or lower (odds ratio, 3.11; P = .0098) and a serum albumin level below 35 g/L (OR, 6.33; P less than .0001).

Baseline predictors for severe anemia (hemoglobin less than 8 g/dL) or blood transfusion included female gender (OR, 2.19; P = .023), no lead-in phase (OR, 2.25; P = .018), age 65 years or older (OR, 3.04; P = .0014), and hemoglobin 12 g/dL or lower for women and 13 g/dL or lower for men (OR, 5.30; P less than .0001),

The study was sponsored by ANRS, the French National Agency for Research in AIDS and Viral Hepatitis, with support from INSERM, the French National Institute for Health and Medical Research. Dr. Hézode said that he has no financial conflicts of interest, but disclosed serving as a speaker and adviser for Abbott, BMS, Gilead, Janssen, Merck, and Roche.

BOSTON – In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial looking at the safety of the regimen.

Although the efficacy of direct-acting antiviral regimens involving the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) combined with pegylated interferon alfa-2a or -2b in combination with ribavirin (PEG-IFN/RBV) in cirrhotic nonresponders to prior therapy was good , their safety was "poor," according to Dr. Christophe Hézode of the Hôpital Henri Mondor in Créteil, France.

Virologic response at 16 weeks in a per-protocol analysis was associated with a virologic response rate of 92% with telaprevir and 77% with boceprevir.

However, there were increased rates of serious adverse events and more difficult-to-manage anemia than in phase III trials for telaprevir and boceprevir, which included only a few patients with cirrhosis, Dr. Hézode said at the annual meeting of the American Association for the Study of Liver Diseases.

In treatment-experienced cirrhotic patients with platelet counts of 100,000/mm³ or serum albumin levels below 35 g/L, clinicians should weigh the risks and benefits of such regimens, with patients treated on a case-by-case basis because of the high risk for severe complications, Dr. Hézode said.

"However, cirrhotic experienced patients without predictors of severe complications clearly should be treated, but cautiously and carefully monitored," he added.

Dr. Hézode and his coinvestigators in the French Cohort of Therapeutic Failure and Resistances in Patients Treated With a Protease Inhibitor (telaprevir or boceprevir), Pegylated Interferon, and Ribavirin (CUPIC) trial studied two cohorts of patients with chronic hepatitis C virus (HCV) infections, and compensated cirrhosis (Child Pugh class A) who had either relapsed or had only a partial response to prior therapy, with partial response defined as at least a 2 log₁₀ decline inV RNA but failure to clear virus by week 24.

He presented data on 497 patients who had completed 16 weeks of therapy on one of two regimens. In one cohort, 292 patients received 12 weeks of telaprevir 750 mg every 8 hours, and PEG-IFN alfa-2a (Pegasys) 180 mcg/wk with ribavirin 1,000-1,200 mg/day, followed by PEG-IFN/RBV through 48 weeks. In the second cohort, patients received a 4-week initiation phase with PEG-IFN alfa-2b (PegIntron) and ribavirin, followed by 44 weeks of boceprevir 800 mg every 8 hours, PEG-IFN 1.5 mcg/kg per wk, and ribavirin 800-1,400 mg/day.

At week 16, 45% of patients on telaprevir had had at least one serious adverse event, with 14.7% terminating therapy because of a serious side effect. In all, nearly one-fourth (22.6%) discontinued therapy, and there were five deaths: from septicemia, septic shock, pneumopathy, endocarditis, and bleeding esophageal varices. Other complications in this group included grade 3 or 4 infections in 6.5%, grade 3 or 4 hepatic decompensation in 2%, grade 3/4 asthenia in 5.5%, and renal failure in 1.7%.

Hematologic adverse events included anemia of grade 2 or greater in 30.4%, erythropoietin use in 53.8%, blood transfusion in 16.1%, and ribavirin dose reduction in 13%. In addition, 2.7% of patients had grade 3 or 4 neutropenia, and 1.7% had grade 3 or 4 thrombocytopenia.

In the boceprevir group, 32.7% had at least one serious adverse event, 26.3% discontinued prematurely, and 7.3% discontinued because of serious events. The cause of one death was described as pneumopathy. Grade 3/4 adverse events involved infections in 2.4%, hepatic decompensation in 2.9%, and asthenia in 5.8%. There were no cases of renal failure in this group.

Hematologic events in patients on boceprevir included grade 2 or greater anemia in 27.8%, erythropoietin use in 46.3%, blood transfusion in 6.3%, and ribavirin dose reduction in 10.7%.

Grade 3/4 neutropenia was seen in 4.4%, and grade 3/4 thrombocytopenia in 5.4%. Two patients (1%) in this cohort received thrombopoietin.

In a multivariate analysis, significant baseline predictors of severe complications (death, severe infection, and hepatic decompensation) included platelet counts of 100,000/mm³ or lower (odds ratio, 3.11; P = .0098) and a serum albumin level below 35 g/L (OR, 6.33; P less than .0001).

Baseline predictors for severe anemia (hemoglobin less than 8 g/dL) or blood transfusion included female gender (OR, 2.19; P = .023), no lead-in phase (OR, 2.25; P = .018), age 65 years or older (OR, 3.04; P = .0014), and hemoglobin 12 g/dL or lower for women and 13 g/dL or lower for men (OR, 5.30; P less than .0001),

The study was sponsored by ANRS, the French National Agency for Research in AIDS and Viral Hepatitis, with support from INSERM, the French National Institute for Health and Medical Research. Dr. Hézode said that he has no financial conflicts of interest, but disclosed serving as a speaker and adviser for Abbott, BMS, Gilead, Janssen, Merck, and Roche.

WASHINGTON – SurgiSIS, a material derived from porcine small intestinal mucosa, can be safely and effectively used for myringoplasty in children, based on data from a prospective, blinded study of 404 patients.

Patients’ tissue is not always available for tympanic membrane repair, and harvesting the graft may increase intraoperative time, said Dr. Riccardo D’Eredita of Vincenza (Italy) Civil Hospital. SurgiSIS (SIS) "promotes early vessel growth, provides scaffolding for remodeling tissues, and is inexpensive and ready to use." He presented the findings at the annual meeting of the American Academy of Otolaryngology – Head and Neck Surgery Foundation.

The material has been used widely in children, and data from previous studies show that SurgiSIS is gradually replaced by host cells, said Dr. D’Eredita. After 30 days, host cells invade SurgiSIS. After 1 year, SurgiSIS is no longer evident, and has been replaced by the patients’ collagen.

In this study, 404 children underwent tympanic membrane repair in 432 ears; 217 were randomized to myringoplasty with SurgiSIS and 215 were randomized to repair using the patients’ own temporalis fascia.

Overall, the group without SurgiSIS had a 97% rate of stable closures and the group with SurgiSIS had a 95% rate. Surgical time was approximately 15 minutes less for SurgiSIS-treated patients, Dr. D’Eredita said.

The researchers assessed the healing of the tympanic membranes over a 10-year period and found comparable reduction of inflammation in the two groups. There were no adverse reactions in the SIS group.

Dr. D’Eredita had no financial conflicts to disclose.

WASHINGTON – SurgiSIS, a material derived from porcine small intestinal mucosa, can be safely and effectively used for myringoplasty in children, based on data from a prospective, blinded study of 404 patients.

Patients’ tissue is not always available for tympanic membrane repair, and harvesting the graft may increase intraoperative time, said Dr. Riccardo D’Eredita of Vincenza (Italy) Civil Hospital. SurgiSIS (SIS) "promotes early vessel growth, provides scaffolding for remodeling tissues, and is inexpensive and ready to use." He presented the findings at the annual meeting of the American Academy of Otolaryngology – Head and Neck Surgery Foundation.

The material has been used widely in children, and data from previous studies show that SurgiSIS is gradually replaced by host cells, said Dr. D’Eredita. After 30 days, host cells invade SurgiSIS. After 1 year, SurgiSIS is no longer evident, and has been replaced by the patients’ collagen.

In this study, 404 children underwent tympanic membrane repair in 432 ears; 217 were randomized to myringoplasty with SurgiSIS and 215 were randomized to repair using the patients’ own temporalis fascia.

Overall, the group without SurgiSIS had a 97% rate of stable closures and the group with SurgiSIS had a 95% rate. Surgical time was approximately 15 minutes less for SurgiSIS-treated patients, Dr. D’Eredita said.

The researchers assessed the healing of the tympanic membranes over a 10-year period and found comparable reduction of inflammation in the two groups. There were no adverse reactions in the SIS group.

Dr. D’Eredita had no financial conflicts to disclose.

WASHINGTON – SurgiSIS, a material derived from porcine small intestinal mucosa, can be safely and effectively used for myringoplasty in children, based on data from a prospective, blinded study of 404 patients.

Patients’ tissue is not always available for tympanic membrane repair, and harvesting the graft may increase intraoperative time, said Dr. Riccardo D’Eredita of Vincenza (Italy) Civil Hospital. SurgiSIS (SIS) "promotes early vessel growth, provides scaffolding for remodeling tissues, and is inexpensive and ready to use." He presented the findings at the annual meeting of the American Academy of Otolaryngology – Head and Neck Surgery Foundation.

The material has been used widely in children, and data from previous studies show that SurgiSIS is gradually replaced by host cells, said Dr. D’Eredita. After 30 days, host cells invade SurgiSIS. After 1 year, SurgiSIS is no longer evident, and has been replaced by the patients’ collagen.

In this study, 404 children underwent tympanic membrane repair in 432 ears; 217 were randomized to myringoplasty with SurgiSIS and 215 were randomized to repair using the patients’ own temporalis fascia.

Overall, the group without SurgiSIS had a 97% rate of stable closures and the group with SurgiSIS had a 95% rate. Surgical time was approximately 15 minutes less for SurgiSIS-treated patients, Dr. D’Eredita said.

The researchers assessed the healing of the tympanic membranes over a 10-year period and found comparable reduction of inflammation in the two groups. There were no adverse reactions in the SIS group.

Dr. D’Eredita had no financial conflicts to disclose.

WASHINGTON – Facial nerve dysfunction affected 23% of 43 children who had parotidectomies in a single-center study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery Foundation.

The findings suggest that facial nerve dysfunction after parotidectomy is common enough in children to merit preoperative counseling, said Dr. James A. Owusu of the University of Minnesota, Minneapolis.

Facial nerve dysfunction rates reported in the literature range from 9% to 60% in adults after parotidectomy, but the condition has not been well studied in children.

Dr. Owusu and his colleagues reviewed the charts of 43 patients younger than age 18 years who underwent parotidectomies at a single tertiary care center between 1999 and 2011. Patients who only had parotid biopsies and those without follow-up data were excluded from the study. The average age of the patients was 4 years, and 58% were girls.

Postoperatively, 33 children (77%) had normal nerve function and 10 (23%) had abnormal nerve function. One patient experienced immediate facial nerve paralysis and nine experienced immediate facial nerve paresis. The marginal mandibular branch was affected in seven patients, the frontal branch in one patient, the buccal branch in one, and both marginal mandibular and frontal branches in one.

The most common diagnosis that led to a parotidectomy was atypical mycobacterium infection (37%), followed by branchial cleft abnormality (19%) and lymphangioma (16%). Nearly all (41) of the children underwent superficial parotidectomy; 2 underwent total parotidectomy.

"Age, gender, and pathologic diagnosis were not predictive of postoperative nerve dysfunction," Dr. Owusu said.

In patients with paresis, full nerve recovery occurred within 1 month for 2 patients, within 2 months for 1 patient, within 6 months for 3 patients, and within 10 months for 2 patients. Final nerve status was not available for 1 patient.

The study was limited by its small size and focus on a single center, Dr. Owusu said.

Dr. Owusu had no financial conflicts to disclose.

WASHINGTON – Facial nerve dysfunction affected 23% of 43 children who had parotidectomies in a single-center study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery Foundation.

The findings suggest that facial nerve dysfunction after parotidectomy is common enough in children to merit preoperative counseling, said Dr. James A. Owusu of the University of Minnesota, Minneapolis.

Facial nerve dysfunction rates reported in the literature range from 9% to 60% in adults after parotidectomy, but the condition has not been well studied in children.

Dr. Owusu and his colleagues reviewed the charts of 43 patients younger than age 18 years who underwent parotidectomies at a single tertiary care center between 1999 and 2011. Patients who only had parotid biopsies and those without follow-up data were excluded from the study. The average age of the patients was 4 years, and 58% were girls.

Postoperatively, 33 children (77%) had normal nerve function and 10 (23%) had abnormal nerve function. One patient experienced immediate facial nerve paralysis and nine experienced immediate facial nerve paresis. The marginal mandibular branch was affected in seven patients, the frontal branch in one patient, the buccal branch in one, and both marginal mandibular and frontal branches in one.

The most common diagnosis that led to a parotidectomy was atypical mycobacterium infection (37%), followed by branchial cleft abnormality (19%) and lymphangioma (16%). Nearly all (41) of the children underwent superficial parotidectomy; 2 underwent total parotidectomy.

"Age, gender, and pathologic diagnosis were not predictive of postoperative nerve dysfunction," Dr. Owusu said.

In patients with paresis, full nerve recovery occurred within 1 month for 2 patients, within 2 months for 1 patient, within 6 months for 3 patients, and within 10 months for 2 patients. Final nerve status was not available for 1 patient.

The study was limited by its small size and focus on a single center, Dr. Owusu said.

Dr. Owusu had no financial conflicts to disclose.

WASHINGTON – Facial nerve dysfunction affected 23% of 43 children who had parotidectomies in a single-center study presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery Foundation.

The findings suggest that facial nerve dysfunction after parotidectomy is common enough in children to merit preoperative counseling, said Dr. James A. Owusu of the University of Minnesota, Minneapolis.

Facial nerve dysfunction rates reported in the literature range from 9% to 60% in adults after parotidectomy, but the condition has not been well studied in children.

Dr. Owusu and his colleagues reviewed the charts of 43 patients younger than age 18 years who underwent parotidectomies at a single tertiary care center between 1999 and 2011. Patients who only had parotid biopsies and those without follow-up data were excluded from the study. The average age of the patients was 4 years, and 58% were girls.

Postoperatively, 33 children (77%) had normal nerve function and 10 (23%) had abnormal nerve function. One patient experienced immediate facial nerve paralysis and nine experienced immediate facial nerve paresis. The marginal mandibular branch was affected in seven patients, the frontal branch in one patient, the buccal branch in one, and both marginal mandibular and frontal branches in one.

The most common diagnosis that led to a parotidectomy was atypical mycobacterium infection (37%), followed by branchial cleft abnormality (19%) and lymphangioma (16%). Nearly all (41) of the children underwent superficial parotidectomy; 2 underwent total parotidectomy.

"Age, gender, and pathologic diagnosis were not predictive of postoperative nerve dysfunction," Dr. Owusu said.

In patients with paresis, full nerve recovery occurred within 1 month for 2 patients, within 2 months for 1 patient, within 6 months for 3 patients, and within 10 months for 2 patients. Final nerve status was not available for 1 patient.

The study was limited by its small size and focus on a single center, Dr. Owusu said.

Dr. Owusu had no financial conflicts to disclose.

CHICAGO – PET/CT scans routinely used in the care of oncology patients may prove useful in pinpointing physiological changes associated with chemo brain.

An analysis of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT images taken before and after chemotherapy in breast cancer patients revealed significant declines in glucose metabolism in two key regions of the brain. The affected areas were the superior medial frontal gyrus and temporal operculum, which are responsible for mental agility, problem solving, daily decision making, sequencing, and long-term memory, Dr. Rachel Lagos reported at the annual meeting of the Radiological Society of North America.

Interestingly, no changes in metabolism were observed in 61 other regions of the brain studied.

"If we can come up with an answer to explain why that is, or to reverse this, then we can solve the problem," Dr. Lagos said in an interview. "The good news is that we already know what these two areas do, so we know at a social level what to prepare women and their families for. We can give them some tools for coping, rather than just a pat on the hand."

Although many cancer patients complain of a mental fog or loss of coping skills, some clinicians remain skeptical without definitive scientific evidence. Previous studies have used magnetic resonance imaging, but this modality only allows clinicians to see anatomic details such as small losses in brain volume. With PET/CT, one can see the effects of chemotherapy on brain function over time, explained Dr. Lagos, a diagnostic radiology resident at West Virginia University in Morgantown.

The retrospective analysis involved PET/CT scans taken at the time of initial cancer staging and 12 months after chemotherapy from 116 women with advanced breast cancer, all of whom also received tamoxifen (Nolvadex, Soltamox). The investigators compared the scans to identify areas of reduced ¹⁸F-FDG uptake, representing lower glucose metabolism, and then plotted the changes as Z-score values. One patient with brain metastases was excluded from the analysis.

Statistically significant declines in glucose metabolism were observed post chemotherapy in the superior medial frontal gyrus as a whole (P = .025), when it was evaluated from left to right (P = .023), and in the temporal operculum (P = .036), Dr. Lagos said.

The investigators did not calculate an average value for the change in Z scores, but the decline in values ranged from 2.5 to 8.0 points, she said.

In 21 patients, the affected regions of the brain regained their metabolism, which corresponds to anecdotal information from patients that chemo brain lifts about 1-2 years after treatment.

"With the small data I’ve been able to accumulate so far, it’s hopeful that this kind of brain phenomenon is temporary," Dr. Lagos said.

The next step is to prospectively assess brain function starting at the time of cancer diagnosis and continuing throughout long-term follow-up, which potentially could lead to improved treatments or prevention, she said. In the meantime, the results provide physiologic evidence for chemo brain, and may prompt peers and counselors to use simple interventions such as creating lists for patients of their daily activities or meal plans to compensate for the mental fog.

Dr. Patrick J. Peller, a radiologist with the Mayo Clinic in Rochester, Minn., who hosted the poster session, said the study provides an understanding of the substrate for the often frustrating symptoms that patients experience, and could facilitate interventions to prevent chemo brain.

"Once you have a way to measure something, it sometimes drives your ability to treat it," he said in an interview. "We don’t have that treatment right now, just like we don’t have treatment for Alzheimer’s disease, but my sense is that it’s possible that our treatment for Alzheimer’s might work in some of these patients because it helps in compensation and not actually changing the underlying disease.

"If it improves the patient’s memory function, it might work in this situation, and you might be able to measure if it’s working with this technique."

Dr. Lagos and Dr. Peller reported no relevant financial disclosures.

CHICAGO – PET/CT scans routinely used in the care of oncology patients may prove useful in pinpointing physiological changes associated with chemo brain.

An analysis of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT images taken before and after chemotherapy in breast cancer patients revealed significant declines in glucose metabolism in two key regions of the brain. The affected areas were the superior medial frontal gyrus and temporal operculum, which are responsible for mental agility, problem solving, daily decision making, sequencing, and long-term memory, Dr. Rachel Lagos reported at the annual meeting of the Radiological Society of North America.

Interestingly, no changes in metabolism were observed in 61 other regions of the brain studied.

"If we can come up with an answer to explain why that is, or to reverse this, then we can solve the problem," Dr. Lagos said in an interview. "The good news is that we already know what these two areas do, so we know at a social level what to prepare women and their families for. We can give them some tools for coping, rather than just a pat on the hand."

Although many cancer patients complain of a mental fog or loss of coping skills, some clinicians remain skeptical without definitive scientific evidence. Previous studies have used magnetic resonance imaging, but this modality only allows clinicians to see anatomic details such as small losses in brain volume. With PET/CT, one can see the effects of chemotherapy on brain function over time, explained Dr. Lagos, a diagnostic radiology resident at West Virginia University in Morgantown.

The retrospective analysis involved PET/CT scans taken at the time of initial cancer staging and 12 months after chemotherapy from 116 women with advanced breast cancer, all of whom also received tamoxifen (Nolvadex, Soltamox). The investigators compared the scans to identify areas of reduced ¹⁸F-FDG uptake, representing lower glucose metabolism, and then plotted the changes as Z-score values. One patient with brain metastases was excluded from the analysis.

Statistically significant declines in glucose metabolism were observed post chemotherapy in the superior medial frontal gyrus as a whole (P = .025), when it was evaluated from left to right (P = .023), and in the temporal operculum (P = .036), Dr. Lagos said.

The investigators did not calculate an average value for the change in Z scores, but the decline in values ranged from 2.5 to 8.0 points, she said.

In 21 patients, the affected regions of the brain regained their metabolism, which corresponds to anecdotal information from patients that chemo brain lifts about 1-2 years after treatment.

"With the small data I’ve been able to accumulate so far, it’s hopeful that this kind of brain phenomenon is temporary," Dr. Lagos said.

The next step is to prospectively assess brain function starting at the time of cancer diagnosis and continuing throughout long-term follow-up, which potentially could lead to improved treatments or prevention, she said. In the meantime, the results provide physiologic evidence for chemo brain, and may prompt peers and counselors to use simple interventions such as creating lists for patients of their daily activities or meal plans to compensate for the mental fog.

Dr. Patrick J. Peller, a radiologist with the Mayo Clinic in Rochester, Minn., who hosted the poster session, said the study provides an understanding of the substrate for the often frustrating symptoms that patients experience, and could facilitate interventions to prevent chemo brain.

"Once you have a way to measure something, it sometimes drives your ability to treat it," he said in an interview. "We don’t have that treatment right now, just like we don’t have treatment for Alzheimer’s disease, but my sense is that it’s possible that our treatment for Alzheimer’s might work in some of these patients because it helps in compensation and not actually changing the underlying disease.

"If it improves the patient’s memory function, it might work in this situation, and you might be able to measure if it’s working with this technique."

Dr. Lagos and Dr. Peller reported no relevant financial disclosures.

CHICAGO – PET/CT scans routinely used in the care of oncology patients may prove useful in pinpointing physiological changes associated with chemo brain.

An analysis of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT images taken before and after chemotherapy in breast cancer patients revealed significant declines in glucose metabolism in two key regions of the brain. The affected areas were the superior medial frontal gyrus and temporal operculum, which are responsible for mental agility, problem solving, daily decision making, sequencing, and long-term memory, Dr. Rachel Lagos reported at the annual meeting of the Radiological Society of North America.

Interestingly, no changes in metabolism were observed in 61 other regions of the brain studied.

"If we can come up with an answer to explain why that is, or to reverse this, then we can solve the problem," Dr. Lagos said in an interview. "The good news is that we already know what these two areas do, so we know at a social level what to prepare women and their families for. We can give them some tools for coping, rather than just a pat on the hand."

Although many cancer patients complain of a mental fog or loss of coping skills, some clinicians remain skeptical without definitive scientific evidence. Previous studies have used magnetic resonance imaging, but this modality only allows clinicians to see anatomic details such as small losses in brain volume. With PET/CT, one can see the effects of chemotherapy on brain function over time, explained Dr. Lagos, a diagnostic radiology resident at West Virginia University in Morgantown.

The retrospective analysis involved PET/CT scans taken at the time of initial cancer staging and 12 months after chemotherapy from 116 women with advanced breast cancer, all of whom also received tamoxifen (Nolvadex, Soltamox). The investigators compared the scans to identify areas of reduced ¹⁸F-FDG uptake, representing lower glucose metabolism, and then plotted the changes as Z-score values. One patient with brain metastases was excluded from the analysis.

Statistically significant declines in glucose metabolism were observed post chemotherapy in the superior medial frontal gyrus as a whole (P = .025), when it was evaluated from left to right (P = .023), and in the temporal operculum (P = .036), Dr. Lagos said.

The investigators did not calculate an average value for the change in Z scores, but the decline in values ranged from 2.5 to 8.0 points, she said.

In 21 patients, the affected regions of the brain regained their metabolism, which corresponds to anecdotal information from patients that chemo brain lifts about 1-2 years after treatment.

"With the small data I’ve been able to accumulate so far, it’s hopeful that this kind of brain phenomenon is temporary," Dr. Lagos said.

The next step is to prospectively assess brain function starting at the time of cancer diagnosis and continuing throughout long-term follow-up, which potentially could lead to improved treatments or prevention, she said. In the meantime, the results provide physiologic evidence for chemo brain, and may prompt peers and counselors to use simple interventions such as creating lists for patients of their daily activities or meal plans to compensate for the mental fog.

Dr. Patrick J. Peller, a radiologist with the Mayo Clinic in Rochester, Minn., who hosted the poster session, said the study provides an understanding of the substrate for the often frustrating symptoms that patients experience, and could facilitate interventions to prevent chemo brain.

"Once you have a way to measure something, it sometimes drives your ability to treat it," he said in an interview. "We don’t have that treatment right now, just like we don’t have treatment for Alzheimer’s disease, but my sense is that it’s possible that our treatment for Alzheimer’s might work in some of these patients because it helps in compensation and not actually changing the underlying disease.

"If it improves the patient’s memory function, it might work in this situation, and you might be able to measure if it’s working with this technique."

Dr. Lagos and Dr. Peller reported no relevant financial disclosures.

Surgical residency programs have not kept up with radical changes in the practice of surgery over the past two decades, but innovations ranging from curriculum reform to increasing the length of residency could help to improve the overall performance of recent surgical residency graduates, according to an analysis in Annals of Surgery.

"The changes that have occurred have been disruptive to residency training, and to date there has been minimal compensation for these," Dr. Frank Lewis and Dr. Mary Klingensmith wrote. "Evidence is now emerging of significant issues in the overall performance of recent graduates from at least three sources – the evaluation of external agents who incorporate these graduates into their practice or group, the opinions of the residents themselves, and the performance of graduates on the oral examination of the American Board of Surgery during the last 8 years" (Ann. Surg. 2012;256:553-59).

The changes include not only the 80-hour workweek for surgical residents, but also clinical areas, according to Dr. Lewis, executive director of the American Board of Surgery, and Dr. Klingensmith, residency program director at Washington University in St. Louis.

The effect of the 80-hour workweek has been a reduction by 6 months to a year of in-hospital experience during 5 years of residency. Most of that reduced time corresponds to night and weekend experience, when residents would be more likely to see urgent and emergent conditions, and to have a greater degree of independent functioning, autonomy, and indirect supervision, they said.

The most significant clinical change has been the development of laparoscopic surgery for intra-abdominal surgical management, which is replacing open surgery and the abdominal incision. Because surgeons in academic settings have been slower to adopt laparoscopy, resident training in the use of this technology has proceeded slowly, they explained.

"While the Residency Review Committee (RRC) for Surgery has been steadily increasing the requirements for surgical resident training, it is still the rule that the most complex laparoscopic surgery is reserved for fellows in postresidency fellowships and not for residents during surgical training, although there is no reason this should be the case," they noted.

In addition, operations performed by general surgeons, and the way in which they are done, have changed significantly in the past 20 years, according to the analysis. For example, the advent of better medical management for benign peptic ulcer disease – along with flexible endoscopy and endoscopic retrograde cholangiopancreatography – means that fewer surgical interventions for peptic ulcer complications and biliary tree stone disease are necessary.

Furthermore, technological innovations have allowed vascular surgeons, rather than general surgeons, to perform most abdominal vascular surgery. Finally, the two surgeons reported, abdominal trauma injuries – which require surgical intervention in 80%-90% of cases – have declined dramatically since 1992.

These types of changes "will undoubtedly continue, and the directions in which surgery will evolve in the future are not predictable," Dr. Lewis and Dr. Klingensmith wrote.

They laid out seven potential ways in which surgical residency programs can address the changes:

• There should be a continuous process to define and continually update the surgical residency curriculum, which needs to keep pace with the fast-changing surgical practice landscape, and to "prune" information related to diseases that no longer are seen frequently in practice.

"The starting point for making changes in residency is to recognize that much of what is being taught is obsolete, and addresses diseases that are no longer a significant problem, or those for which surgical treatment is rarely needed," they said.

• Residency programs should improve the efficacy of resident learning by reducing clerical functions for residents, using physician extenders where appropriate, and utilizing mobile computing technology to deliver "a more defined and comprehensive curriculum to residents at an individual level."

• Educators could make better use of simulators in certain areas, such as laparoscopic surgery and endoscopic surgery.

• There should be an earlier specialty focus in residency training for those surgical residents who already know which specialty they would like to pursue.

• Surgical residency should include expanded laparoscopic surgery training.

• Residency programs could increase in length to make up for the time lost to the 80-hour workweek rule. Four-fifths of surgical residents already elect to take a postresidency fellowship in a specialty or subspecialty area, so "any discussion of extending residency only applies to the 20% of residents who currently complete only general surgical residency and do not seek subspecialty training," they said. "Extending residency by 1 year to obtain more extensive training in general surgery per se would not seem to be an insurmountable issue if the benefits clearly warranted it."

• Surgical training should expand to include additional skills, such as the use of ultrasound for better diagnosis of conditions in breast, endocrine, vascular, and trauma diseases and the use of interventional catheter techniques for the diagnosis or treatment of a variety of conditions.

It’s not possible to reverse the changes that have occurred over the past 2 decades, and in fact the workweek could see further shortening, as has happened in Europe, the investigators noted. "The most effective way in which to address the changes is therefore to look at the things which can be changed in resident training, the many areas in which improvements in resident teaching are possible, and the areas in which residents’ capabilities could be productively expanded."

The investigators did not report any conflicts of interest.

Surgical residency programs have not kept up with radical changes in the practice of surgery over the past two decades, but innovations ranging from curriculum reform to increasing the length of residency could help to improve the overall performance of recent surgical residency graduates, according to an analysis in Annals of Surgery.

"The changes that have occurred have been disruptive to residency training, and to date there has been minimal compensation for these," Dr. Frank Lewis and Dr. Mary Klingensmith wrote. "Evidence is now emerging of significant issues in the overall performance of recent graduates from at least three sources – the evaluation of external agents who incorporate these graduates into their practice or group, the opinions of the residents themselves, and the performance of graduates on the oral examination of the American Board of Surgery during the last 8 years" (Ann. Surg. 2012;256:553-59).

The changes include not only the 80-hour workweek for surgical residents, but also clinical areas, according to Dr. Lewis, executive director of the American Board of Surgery, and Dr. Klingensmith, residency program director at Washington University in St. Louis.

The effect of the 80-hour workweek has been a reduction by 6 months to a year of in-hospital experience during 5 years of residency. Most of that reduced time corresponds to night and weekend experience, when residents would be more likely to see urgent and emergent conditions, and to have a greater degree of independent functioning, autonomy, and indirect supervision, they said.

The most significant clinical change has been the development of laparoscopic surgery for intra-abdominal surgical management, which is replacing open surgery and the abdominal incision. Because surgeons in academic settings have been slower to adopt laparoscopy, resident training in the use of this technology has proceeded slowly, they explained.

"While the Residency Review Committee (RRC) for Surgery has been steadily increasing the requirements for surgical resident training, it is still the rule that the most complex laparoscopic surgery is reserved for fellows in postresidency fellowships and not for residents during surgical training, although there is no reason this should be the case," they noted.

In addition, operations performed by general surgeons, and the way in which they are done, have changed significantly in the past 20 years, according to the analysis. For example, the advent of better medical management for benign peptic ulcer disease – along with flexible endoscopy and endoscopic retrograde cholangiopancreatography – means that fewer surgical interventions for peptic ulcer complications and biliary tree stone disease are necessary.

Furthermore, technological innovations have allowed vascular surgeons, rather than general surgeons, to perform most abdominal vascular surgery. Finally, the two surgeons reported, abdominal trauma injuries – which require surgical intervention in 80%-90% of cases – have declined dramatically since 1992.

These types of changes "will undoubtedly continue, and the directions in which surgery will evolve in the future are not predictable," Dr. Lewis and Dr. Klingensmith wrote.

They laid out seven potential ways in which surgical residency programs can address the changes:

• There should be a continuous process to define and continually update the surgical residency curriculum, which needs to keep pace with the fast-changing surgical practice landscape, and to "prune" information related to diseases that no longer are seen frequently in practice.

"The starting point for making changes in residency is to recognize that much of what is being taught is obsolete, and addresses diseases that are no longer a significant problem, or those for which surgical treatment is rarely needed," they said.

• Residency programs should improve the efficacy of resident learning by reducing clerical functions for residents, using physician extenders where appropriate, and utilizing mobile computing technology to deliver "a more defined and comprehensive curriculum to residents at an individual level."

• Educators could make better use of simulators in certain areas, such as laparoscopic surgery and endoscopic surgery.

• There should be an earlier specialty focus in residency training for those surgical residents who already know which specialty they would like to pursue.

• Surgical residency should include expanded laparoscopic surgery training.

• Residency programs could increase in length to make up for the time lost to the 80-hour workweek rule. Four-fifths of surgical residents already elect to take a postresidency fellowship in a specialty or subspecialty area, so "any discussion of extending residency only applies to the 20% of residents who currently complete only general surgical residency and do not seek subspecialty training," they said. "Extending residency by 1 year to obtain more extensive training in general surgery per se would not seem to be an insurmountable issue if the benefits clearly warranted it."

• Surgical training should expand to include additional skills, such as the use of ultrasound for better diagnosis of conditions in breast, endocrine, vascular, and trauma diseases and the use of interventional catheter techniques for the diagnosis or treatment of a variety of conditions.

It’s not possible to reverse the changes that have occurred over the past 2 decades, and in fact the workweek could see further shortening, as has happened in Europe, the investigators noted. "The most effective way in which to address the changes is therefore to look at the things which can be changed in resident training, the many areas in which improvements in resident teaching are possible, and the areas in which residents’ capabilities could be productively expanded."

The investigators did not report any conflicts of interest.

Surgical residency programs have not kept up with radical changes in the practice of surgery over the past two decades, but innovations ranging from curriculum reform to increasing the length of residency could help to improve the overall performance of recent surgical residency graduates, according to an analysis in Annals of Surgery.

"The changes that have occurred have been disruptive to residency training, and to date there has been minimal compensation for these," Dr. Frank Lewis and Dr. Mary Klingensmith wrote. "Evidence is now emerging of significant issues in the overall performance of recent graduates from at least three sources – the evaluation of external agents who incorporate these graduates into their practice or group, the opinions of the residents themselves, and the performance of graduates on the oral examination of the American Board of Surgery during the last 8 years" (Ann. Surg. 2012;256:553-59).

The changes include not only the 80-hour workweek for surgical residents, but also clinical areas, according to Dr. Lewis, executive director of the American Board of Surgery, and Dr. Klingensmith, residency program director at Washington University in St. Louis.

The effect of the 80-hour workweek has been a reduction by 6 months to a year of in-hospital experience during 5 years of residency. Most of that reduced time corresponds to night and weekend experience, when residents would be more likely to see urgent and emergent conditions, and to have a greater degree of independent functioning, autonomy, and indirect supervision, they said.

The most significant clinical change has been the development of laparoscopic surgery for intra-abdominal surgical management, which is replacing open surgery and the abdominal incision. Because surgeons in academic settings have been slower to adopt laparoscopy, resident training in the use of this technology has proceeded slowly, they explained.

"While the Residency Review Committee (RRC) for Surgery has been steadily increasing the requirements for surgical resident training, it is still the rule that the most complex laparoscopic surgery is reserved for fellows in postresidency fellowships and not for residents during surgical training, although there is no reason this should be the case," they noted.

In addition, operations performed by general surgeons, and the way in which they are done, have changed significantly in the past 20 years, according to the analysis. For example, the advent of better medical management for benign peptic ulcer disease – along with flexible endoscopy and endoscopic retrograde cholangiopancreatography – means that fewer surgical interventions for peptic ulcer complications and biliary tree stone disease are necessary.

Furthermore, technological innovations have allowed vascular surgeons, rather than general surgeons, to perform most abdominal vascular surgery. Finally, the two surgeons reported, abdominal trauma injuries – which require surgical intervention in 80%-90% of cases – have declined dramatically since 1992.

These types of changes "will undoubtedly continue, and the directions in which surgery will evolve in the future are not predictable," Dr. Lewis and Dr. Klingensmith wrote.

They laid out seven potential ways in which surgical residency programs can address the changes:

• There should be a continuous process to define and continually update the surgical residency curriculum, which needs to keep pace with the fast-changing surgical practice landscape, and to "prune" information related to diseases that no longer are seen frequently in practice.

"The starting point for making changes in residency is to recognize that much of what is being taught is obsolete, and addresses diseases that are no longer a significant problem, or those for which surgical treatment is rarely needed," they said.

• Residency programs should improve the efficacy of resident learning by reducing clerical functions for residents, using physician extenders where appropriate, and utilizing mobile computing technology to deliver "a more defined and comprehensive curriculum to residents at an individual level."

• Educators could make better use of simulators in certain areas, such as laparoscopic surgery and endoscopic surgery.

• There should be an earlier specialty focus in residency training for those surgical residents who already know which specialty they would like to pursue.

• Surgical residency should include expanded laparoscopic surgery training.

• Residency programs could increase in length to make up for the time lost to the 80-hour workweek rule. Four-fifths of surgical residents already elect to take a postresidency fellowship in a specialty or subspecialty area, so "any discussion of extending residency only applies to the 20% of residents who currently complete only general surgical residency and do not seek subspecialty training," they said. "Extending residency by 1 year to obtain more extensive training in general surgery per se would not seem to be an insurmountable issue if the benefits clearly warranted it."

• Surgical training should expand to include additional skills, such as the use of ultrasound for better diagnosis of conditions in breast, endocrine, vascular, and trauma diseases and the use of interventional catheter techniques for the diagnosis or treatment of a variety of conditions.

It’s not possible to reverse the changes that have occurred over the past 2 decades, and in fact the workweek could see further shortening, as has happened in Europe, the investigators noted. "The most effective way in which to address the changes is therefore to look at the things which can be changed in resident training, the many areas in which improvements in resident teaching are possible, and the areas in which residents’ capabilities could be productively expanded."

The investigators did not report any conflicts of interest.