Conference Coverage

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.

“A more abnormal aging course was seen among those with continuing active epilepsy, those with focal epilepsy compared with generalized epilepsies, and those who had the highest lifetime load of specific anti-epilepsy medications,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.

The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).

In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)

Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”

The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).

For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.

The researchers report these findings:

• Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
• Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
• The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
• Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)

The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.

From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.

It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”

The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”

The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.

Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.

This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.

While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.

“A more abnormal aging course was seen among those with continuing active epilepsy, those with focal epilepsy compared with generalized epilepsies, and those who had the highest lifetime load of specific anti-epilepsy medications,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.

The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).

In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)

Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”

The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).

For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.

The researchers report these findings:

• Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
• Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
• The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
• Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)

The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.

From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.

It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”

The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”

The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.

Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.

This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.

While the meaning of the findings aren’t entirely clear, new research offers insight into the aging brains of people who developed child-onset epilepsy: A cohort with an average age of 63 appears to be more likely than controls to show signs of brain deterioration, according to a study presented at the annual meeting of the American Epilepsy Society.

“A more abnormal aging course was seen among those with continuing active epilepsy, those with focal epilepsy compared with generalized epilepsies, and those who had the highest lifetime load of specific anti-epilepsy medications,” lead author Matti Sillanpää, MD, PhD, a researcher and former child neurologist based at the University of Turko in Finland, said in an interview.

The study began 60 years ago when Finnish researchers started to track 99 subjects who were under 16 and had developed uncomplicated epilepsy. In 2012, 51 participants returned for assessments (9 of the original cohort had died, 2 didn’t speak Finnish as a mother tongue, and 15 had left the country or couldn’t be found).

In 2017, 41 participants agreed to take part in follow-up assessments (1 of the 2012 cohort could not be traced, and 9 declined to participate.)

Researchers launched the follow-up assessments to provide more insight into aging and epilepsy, Dr. Sillanpää said. “While we are in the early stages of understanding the brain and cognitive aging processes of people with epilepsy, there are enough worrisome signs from neuroimaging and cognitive studies to suggest that much more clinical and research attention is warranted. Especially important are population-based investigations that include persons with both remitted as well as active epilepsy in order to obtain a clearer understanding of the overall aging risks involved.”

The average age of the 41 subjects in the second assessment was 63.2 (4.1), and 58% were female. Just over half (52%) had focal epilepsy, and 48% had generalized epilepsy. In 74%, epilepsy had remitted, and it remained active in the rest (26%).

For the study, researchers compared the subjects with a control group of 46 subjects, 50% of whom were female, with an average age of 63.0 (4.13). The original control group had 99 participants, and 52 took part in 2012. Of those, 6 declined to participate in the 2017 assessments.

The researchers report these findings:

• Patients with active epilepsy were more likely to have neurologic signs than were those with remitted epilepsy (P = .015), especially the most common signs – cerebellar signs (P < .001). There was a trend toward cerebellar atrophy but it wasn’t statistically significant (P = .06).
• Patients with focal epilepsies were more likely to have neurologic signs (P = .008) and, specifically, cerebellar signs (P = .018) than were those with generalized epilepsies.
• The study authors calculated the lifetime usage of four drugs: carbamazepine, diphenylhydantoin, phenobarbital, and valproate. They found that patients with higher usage had more peripheral neuropathy, especially those with high levels of diphenylhydantoin, and phenobarbital usage.
• Overall, patients with epilepsy versus controls and those with active epilepsy versus remitting epilepsy were more likely to show adjusted declines in “cognitive trajectories” (both P < .05)

The researchers also estimated beta-amyloid levels via Pittsburgh Compound B positron emission tomography (PIB-PET); some specialists consider PIB-positive levels to be a sign of more beta amyloid.

From 2012 to 2017, the percentage of patients with epilepsy who were PIB positive grew from 22% to 33% (P = .03), while the percentage grew from 7% to 11% in the controls (P = .04). “The presence of amyloid and increasing positivity is cause for concern, and further research into the course of the participants is critical,” Dr. Sillanpää said.

It’s not clear if higher levels of brain aging are affecting the lives of participants, he said. “No one in the cohort has a diagnosed dementia at present, but going forward it will be important to pay close attention to the day-to-day functional status of participants.”

The mechanisms that may cause more brain aging in epilepsy aren’t known. However, “the CDC has shown through population-based investigations that people with epilepsy as a group may be more socially isolated, more physically inactive, and may harbor other lifestyle issues that we now know to be counterproductive to successful cognitive and brain aging in the general population,” Dr. Sillanpää said. “These factors need to be examined in depth in aging persons with epilepsy to gain a sound understanding of the risk and resilience factors that are most important so that people with epilepsy can act accordingly.”

The researchers also report that in patients with epilepsy, there’s evidence of a link between hypertension and hippocampal atrophy. They reported trends toward links between obesity and ischemic disease and between type 2 diabetes and hippocampal atrophy.

Going forward, “the findings may be helpful in the treatment and counseling of patients with epilepsy and especially advocating for those health and lifestyle practices that may be beneficial to long-term courses,” Dr. Sillanpää said. As for the study cohort, he said, researchers plan to continue monitoring them to track their long-term outcomes and any development of neurological disorders such as Alzheimer’s disease.

This work was funded by CURE Epilepsy, the National Governmental Research Grant, and the Pro Humanitate Foundation Grant. The study authors report no disclosures.

Fibrosis-4 index (FIB-4) scores are strongly associated with severe liver disease outcomes in a primary care population, both in patients with known chronic liver disease and those without known CLD. The result could help identify patients with CLD before their condition becomes severe.

Digital Vision/Thinkstock

FIB-4 has previously shown utility in predicting the risk of advanced fibrosis in patients with viral hepatitis B and C, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol-related liver disease.

“This is really important in primary care because FIB-4 is easy to calculate. Its inputs are accessible, and it is inexpensive, often taking advantage of labs that we’ve ordered anyway. And if we can use it to find advanced fibrosis, it will be critically important because we know that advanced fibrosis is associated with severe liver outcomes – these are going to be patients that we need to make sure are in touch with our hepatology colleagues,” said Andrew Schreiner, MD, during a presentation of the results at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Schreiner is general internist at the Medical University of South Carolina, Charleston.

He also noted that FIB-4 is playing an important role in the assessment of NAFLD and NASH. Many newer algorithms to manage NAFLD in the primary care setting rely on FIB-4, but that application is limited because NAFLD is underdiagnosed according to administrative database studies, which found rates of about 2%-5% despite the fact that estimates put it at having a prevalence of 25%-30% in the U.S. population.

To determine if FIB-4 scores could assist in identifying primary care patients at risk of severe outcomes, including cirrhosis, hepatocellular carcinoma, and liver transplant, the researchers conducted a retrospective analysis of primary care electronic health care data from 20,556 patients between 2007 and 2018 who were seen at their institution. Participants had ALT and AST values less than 500 IU/L, as well as a platelet count within two months preceding or on the day of the liver enzyme tests. They excluded individuals with known chronic or severe liver disease.

65% of patients were female, 45% were Black, and the mean BMI was 29.8 kg/m2. 64% of participants were ranked as low risk (FIB-4 ≤1.3), 29% with undetermined risk (1.3-2.67), and 7% with high risk (>2.67).

The population had more liver risk than expected. “[It is] a distribution that certainly may have more high risk and indeterminant risks than we would have anticipated, but we have seen this in external studies,” said Dr. Schreiner.

Over a mean follow-up period of 8.2 years, 11% were diagnosed with CLD: 2.3% developed NAFLD, 8.2% another CLD, and 0.5% had NAFLD and another CLD. About 4% developed a severe CLD. A severe liver outcome occurred in 2.2% of those who had been classified as FIB-4 low risk, 4.2% classified as indeterminate risk, and 20.8% of those classified as high risk.

“Troublingly,” said Dr. Schreiner, 49% of those who went on to develop a severe liver outcome had no CLD diagnosis before it occurred. “This is a tremendous opportunity to improve diagnosis in this setting.”

After adjustment for race, gender, marital status, smoking history, BMI, and various comorbidities, the researchers found a higher risk of severe liver disease associated with indeterminate FIB-4 risk score (hazard ratio, 1.62; 95% confidence interval, 1.36-1.92) and a high FIB-4 risk score (HR, 6.64; 95% CI, 5.58-7.90), compared with those with a low FIB-4 risk score. The same was true for individual liver diseases, including NAFLD (indeterminate HR, 1.88; 95% CI, 0.99-3.60; high HR, 7.32; 95% CI, 3.44-15.58), other liver diagnosis (indeterminate HR, 2.65; 95% CI, 1.93-3.63; high HR, 11.39; 95% CI, 8.53-15.20), and NAFLD plus another liver disease (intermediate HR, 2.53; 95% CI, 0.79-8.12; high HR, 6.89; 95% CI, 1.82-26.14).

Dr. Schreiner conceded that the study may not be generalizable, since FIB-4 was not designed for use in general populations, and it was conducted at a single center.

During the question-and-answer session after the talk, Dr. Schreiner was asked if the majority of the 49% who had a severe liver outcome without previous liver disease had NAFLD. He said that was the team’s hypothesis, and they are in the process of examining that data, but a significant number appear to be alcohol related. “For us in the primary care setting, it’s just another opportunity to emphasize that we have to do a better job getting exposure histories, and alcohol histories in particular, and finding ways to document those in ways that we can make diagnoses for patients and for our hepatology colleagues,” said Dr. Schreiner.

Comoderator Kathleen Corey, MD, asked Dr. Schreiner if he had any concerns about false positives from FIB-4 screening, and whether that could lead to overtreatment. “We’ve seen other screening tests leading to patient distress and overutilization of resources. How do you think we might be able to mitigate that?” asked Dr. Corey, who is an assistant professor of medicine at Harvard Medical School and director of the Fatty Liver Clinic at Massachusetts General Hospital, both in Boston.

Dr. Schreiner underscored the need for more physician education about FIB-4, both its potential and its pitfalls, since many primary care providers don’t use it or even know about it. “FIB-4 is very popular in the hepatology literature, but in primary care, we don’t talk about it as often. So I think educational efforts about its possible utility, about some of the drawbacks, or some of the things that might lead to inappropriately positive results – like advanced age, for those of us who see patients 60 and older. Those are really important considerations both for the patient and the provider for management of expectations and concerns. I’m worried too about application in our younger cohorts. The explosion of NAFLD in adolescence, and the likelihood that we might get a false negative in maybe a 28-year-old who might have problematic disease, is a concern as well,” said Dr. Schreiner.

Dr. Schreiner has no relevant financial disclosures. Dr. Corey has been on an advisory committee or review panel for Bristol-Myers Squibb, Novo Nordisk, and Gilead. She has consulted for Novo Nordisk and received research support from BMS, Boehringer Ingelheim, Novartis, and Boehringer Ingelheim.

Fibrosis-4 index (FIB-4) scores are strongly associated with severe liver disease outcomes in a primary care population, both in patients with known chronic liver disease and those without known CLD. The result could help identify patients with CLD before their condition becomes severe.

Digital Vision/Thinkstock

FIB-4 has previously shown utility in predicting the risk of advanced fibrosis in patients with viral hepatitis B and C, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol-related liver disease.

“This is really important in primary care because FIB-4 is easy to calculate. Its inputs are accessible, and it is inexpensive, often taking advantage of labs that we’ve ordered anyway. And if we can use it to find advanced fibrosis, it will be critically important because we know that advanced fibrosis is associated with severe liver outcomes – these are going to be patients that we need to make sure are in touch with our hepatology colleagues,” said Andrew Schreiner, MD, during a presentation of the results at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Schreiner is general internist at the Medical University of South Carolina, Charleston.

He also noted that FIB-4 is playing an important role in the assessment of NAFLD and NASH. Many newer algorithms to manage NAFLD in the primary care setting rely on FIB-4, but that application is limited because NAFLD is underdiagnosed according to administrative database studies, which found rates of about 2%-5% despite the fact that estimates put it at having a prevalence of 25%-30% in the U.S. population.

To determine if FIB-4 scores could assist in identifying primary care patients at risk of severe outcomes, including cirrhosis, hepatocellular carcinoma, and liver transplant, the researchers conducted a retrospective analysis of primary care electronic health care data from 20,556 patients between 2007 and 2018 who were seen at their institution. Participants had ALT and AST values less than 500 IU/L, as well as a platelet count within two months preceding or on the day of the liver enzyme tests. They excluded individuals with known chronic or severe liver disease.

65% of patients were female, 45% were Black, and the mean BMI was 29.8 kg/m2. 64% of participants were ranked as low risk (FIB-4 ≤1.3), 29% with undetermined risk (1.3-2.67), and 7% with high risk (>2.67).

The population had more liver risk than expected. “[It is] a distribution that certainly may have more high risk and indeterminant risks than we would have anticipated, but we have seen this in external studies,” said Dr. Schreiner.

Over a mean follow-up period of 8.2 years, 11% were diagnosed with CLD: 2.3% developed NAFLD, 8.2% another CLD, and 0.5% had NAFLD and another CLD. About 4% developed a severe CLD. A severe liver outcome occurred in 2.2% of those who had been classified as FIB-4 low risk, 4.2% classified as indeterminate risk, and 20.8% of those classified as high risk.

“Troublingly,” said Dr. Schreiner, 49% of those who went on to develop a severe liver outcome had no CLD diagnosis before it occurred. “This is a tremendous opportunity to improve diagnosis in this setting.”

After adjustment for race, gender, marital status, smoking history, BMI, and various comorbidities, the researchers found a higher risk of severe liver disease associated with indeterminate FIB-4 risk score (hazard ratio, 1.62; 95% confidence interval, 1.36-1.92) and a high FIB-4 risk score (HR, 6.64; 95% CI, 5.58-7.90), compared with those with a low FIB-4 risk score. The same was true for individual liver diseases, including NAFLD (indeterminate HR, 1.88; 95% CI, 0.99-3.60; high HR, 7.32; 95% CI, 3.44-15.58), other liver diagnosis (indeterminate HR, 2.65; 95% CI, 1.93-3.63; high HR, 11.39; 95% CI, 8.53-15.20), and NAFLD plus another liver disease (intermediate HR, 2.53; 95% CI, 0.79-8.12; high HR, 6.89; 95% CI, 1.82-26.14).

Dr. Schreiner conceded that the study may not be generalizable, since FIB-4 was not designed for use in general populations, and it was conducted at a single center.

During the question-and-answer session after the talk, Dr. Schreiner was asked if the majority of the 49% who had a severe liver outcome without previous liver disease had NAFLD. He said that was the team’s hypothesis, and they are in the process of examining that data, but a significant number appear to be alcohol related. “For us in the primary care setting, it’s just another opportunity to emphasize that we have to do a better job getting exposure histories, and alcohol histories in particular, and finding ways to document those in ways that we can make diagnoses for patients and for our hepatology colleagues,” said Dr. Schreiner.

Comoderator Kathleen Corey, MD, asked Dr. Schreiner if he had any concerns about false positives from FIB-4 screening, and whether that could lead to overtreatment. “We’ve seen other screening tests leading to patient distress and overutilization of resources. How do you think we might be able to mitigate that?” asked Dr. Corey, who is an assistant professor of medicine at Harvard Medical School and director of the Fatty Liver Clinic at Massachusetts General Hospital, both in Boston.

Dr. Schreiner underscored the need for more physician education about FIB-4, both its potential and its pitfalls, since many primary care providers don’t use it or even know about it. “FIB-4 is very popular in the hepatology literature, but in primary care, we don’t talk about it as often. So I think educational efforts about its possible utility, about some of the drawbacks, or some of the things that might lead to inappropriately positive results – like advanced age, for those of us who see patients 60 and older. Those are really important considerations both for the patient and the provider for management of expectations and concerns. I’m worried too about application in our younger cohorts. The explosion of NAFLD in adolescence, and the likelihood that we might get a false negative in maybe a 28-year-old who might have problematic disease, is a concern as well,” said Dr. Schreiner.

Dr. Schreiner has no relevant financial disclosures. Dr. Corey has been on an advisory committee or review panel for Bristol-Myers Squibb, Novo Nordisk, and Gilead. She has consulted for Novo Nordisk and received research support from BMS, Boehringer Ingelheim, Novartis, and Boehringer Ingelheim.

Fibrosis-4 index (FIB-4) scores are strongly associated with severe liver disease outcomes in a primary care population, both in patients with known chronic liver disease and those without known CLD. The result could help identify patients with CLD before their condition becomes severe.

Digital Vision/Thinkstock

FIB-4 has previously shown utility in predicting the risk of advanced fibrosis in patients with viral hepatitis B and C, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol-related liver disease.

“This is really important in primary care because FIB-4 is easy to calculate. Its inputs are accessible, and it is inexpensive, often taking advantage of labs that we’ve ordered anyway. And if we can use it to find advanced fibrosis, it will be critically important because we know that advanced fibrosis is associated with severe liver outcomes – these are going to be patients that we need to make sure are in touch with our hepatology colleagues,” said Andrew Schreiner, MD, during a presentation of the results at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Schreiner is general internist at the Medical University of South Carolina, Charleston.

He also noted that FIB-4 is playing an important role in the assessment of NAFLD and NASH. Many newer algorithms to manage NAFLD in the primary care setting rely on FIB-4, but that application is limited because NAFLD is underdiagnosed according to administrative database studies, which found rates of about 2%-5% despite the fact that estimates put it at having a prevalence of 25%-30% in the U.S. population.

To determine if FIB-4 scores could assist in identifying primary care patients at risk of severe outcomes, including cirrhosis, hepatocellular carcinoma, and liver transplant, the researchers conducted a retrospective analysis of primary care electronic health care data from 20,556 patients between 2007 and 2018 who were seen at their institution. Participants had ALT and AST values less than 500 IU/L, as well as a platelet count within two months preceding or on the day of the liver enzyme tests. They excluded individuals with known chronic or severe liver disease.

65% of patients were female, 45% were Black, and the mean BMI was 29.8 kg/m2. 64% of participants were ranked as low risk (FIB-4 ≤1.3), 29% with undetermined risk (1.3-2.67), and 7% with high risk (>2.67).

The population had more liver risk than expected. “[It is] a distribution that certainly may have more high risk and indeterminant risks than we would have anticipated, but we have seen this in external studies,” said Dr. Schreiner.

Over a mean follow-up period of 8.2 years, 11% were diagnosed with CLD: 2.3% developed NAFLD, 8.2% another CLD, and 0.5% had NAFLD and another CLD. About 4% developed a severe CLD. A severe liver outcome occurred in 2.2% of those who had been classified as FIB-4 low risk, 4.2% classified as indeterminate risk, and 20.8% of those classified as high risk.

“Troublingly,” said Dr. Schreiner, 49% of those who went on to develop a severe liver outcome had no CLD diagnosis before it occurred. “This is a tremendous opportunity to improve diagnosis in this setting.”

After adjustment for race, gender, marital status, smoking history, BMI, and various comorbidities, the researchers found a higher risk of severe liver disease associated with indeterminate FIB-4 risk score (hazard ratio, 1.62; 95% confidence interval, 1.36-1.92) and a high FIB-4 risk score (HR, 6.64; 95% CI, 5.58-7.90), compared with those with a low FIB-4 risk score. The same was true for individual liver diseases, including NAFLD (indeterminate HR, 1.88; 95% CI, 0.99-3.60; high HR, 7.32; 95% CI, 3.44-15.58), other liver diagnosis (indeterminate HR, 2.65; 95% CI, 1.93-3.63; high HR, 11.39; 95% CI, 8.53-15.20), and NAFLD plus another liver disease (intermediate HR, 2.53; 95% CI, 0.79-8.12; high HR, 6.89; 95% CI, 1.82-26.14).

Dr. Schreiner conceded that the study may not be generalizable, since FIB-4 was not designed for use in general populations, and it was conducted at a single center.

During the question-and-answer session after the talk, Dr. Schreiner was asked if the majority of the 49% who had a severe liver outcome without previous liver disease had NAFLD. He said that was the team’s hypothesis, and they are in the process of examining that data, but a significant number appear to be alcohol related. “For us in the primary care setting, it’s just another opportunity to emphasize that we have to do a better job getting exposure histories, and alcohol histories in particular, and finding ways to document those in ways that we can make diagnoses for patients and for our hepatology colleagues,” said Dr. Schreiner.

Comoderator Kathleen Corey, MD, asked Dr. Schreiner if he had any concerns about false positives from FIB-4 screening, and whether that could lead to overtreatment. “We’ve seen other screening tests leading to patient distress and overutilization of resources. How do you think we might be able to mitigate that?” asked Dr. Corey, who is an assistant professor of medicine at Harvard Medical School and director of the Fatty Liver Clinic at Massachusetts General Hospital, both in Boston.

Dr. Schreiner underscored the need for more physician education about FIB-4, both its potential and its pitfalls, since many primary care providers don’t use it or even know about it. “FIB-4 is very popular in the hepatology literature, but in primary care, we don’t talk about it as often. So I think educational efforts about its possible utility, about some of the drawbacks, or some of the things that might lead to inappropriately positive results – like advanced age, for those of us who see patients 60 and older. Those are really important considerations both for the patient and the provider for management of expectations and concerns. I’m worried too about application in our younger cohorts. The explosion of NAFLD in adolescence, and the likelihood that we might get a false negative in maybe a 28-year-old who might have problematic disease, is a concern as well,” said Dr. Schreiner.

Dr. Schreiner has no relevant financial disclosures. Dr. Corey has been on an advisory committee or review panel for Bristol-Myers Squibb, Novo Nordisk, and Gilead. She has consulted for Novo Nordisk and received research support from BMS, Boehringer Ingelheim, Novartis, and Boehringer Ingelheim.

Adjuvant treatment with metformin did not improve outcomes in most patients with early breast cancer, according to new findings from a randomized controlled trial.

In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”

However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.

In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).

The findings were presented at the San Antonio Breast Cancer Symposium.

“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.

Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”

In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.

The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
 

No benefit seen

Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.

In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.

After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).

Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.

In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.

There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).

There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).

Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
 

Possible HER2 advantage

However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.

There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.

In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).

“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
 

More research?

Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.

“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.

“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”

The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.

A version of this article first appeared on Medscape.com.

Adjuvant treatment with metformin did not improve outcomes in most patients with early breast cancer, according to new findings from a randomized controlled trial.

In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”

However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.

In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).

The findings were presented at the San Antonio Breast Cancer Symposium.

“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.

Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”

In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.

The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
 

No benefit seen

Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.

In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.

After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).

Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.

In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.

There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).

There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).

Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
 

Possible HER2 advantage

However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.

There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.

In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).

“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
 

More research?

Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.

“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.

“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”

The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.

A version of this article first appeared on Medscape.com.

Adjuvant treatment with metformin did not improve outcomes in most patients with early breast cancer, according to new findings from a randomized controlled trial.

In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”

However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.

In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).

The findings were presented at the San Antonio Breast Cancer Symposium.

“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.

Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”

In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.

The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
 

No benefit seen

Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.

In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.

After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).

Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.

In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.

There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).

There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).

Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
 

Possible HER2 advantage

However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.

There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.

In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).

“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
 

More research?

Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.

“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.

“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”

The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.

A version of this article first appeared on Medscape.com.

The number of adverse events involving vascular necrosis and vision changes following injection of dermal fillers increased from 2014 to 2020, results from a large database analysis showed.

“The ASDS estimates that 1.6 million soft tissue filler procedures were performed in 2019, a 78% increase from 2012,” presenting author Michelle Xiong, a 4th-year student at Brown University, Providence, R.I., said during a virtual abstract session at the annual meeting of the American Society for Dermatologic Surgery. “The popularity of dermal fillers continues to increase. With that, there is increasing concern of possible associated adverse events. Most concerning are those related to vascular occlusion.”

Under the supervision of senior author Kachiu C. Lee, MD, MPH, of Main Line Center for Laser Surgery in Ardmore, Pa., Ms. Xiong and colleagues analyzed the Food and Drug Administration’s Manufacturer and User Facility Device Experience (MAUDE) database of medical device–related adverse event reports, to better understand and characterize dermal filler-related complications. They limited the analysis to adverse events involving injectable fillers from January 2014 to December 2020 and determined the number of complications by type per year and reviewed reports to identify injection site locations. Next, they used the binomial test to compare the proportion of complication categories from 2014 through 2016 and from 2017 through 2020.

In all, 5,994 reports were identified during the 7-year study period. To evaluate trends over time, the researchers estimated the rate of complications per 100 reports each year. While the absolute number of reports increased over time, the rate of adverse events per 100 reports decreased, suggesting an overall improvement in safety.

When the researchers focused on complications involving vascular occlusion, they found that vascular necrosis accounted for 3.5% of all complications, compared with vision changes (1.5% of all complications), and stroke (0.3% of all complications). When comparing the years 2014-2016 with 2017-2020, there was a significant increase in adverse events involving vascular necrosis (0.9%; P = .018) and vision changes (0.94%; P = .001), but no significant difference in the number of reports of stroke (-0.1%; P = .409). “This highlights that serious complications like necrosis and vision changes have increased over time,” Ms. Xiong said.

Overall, the three most common injection sites involving necrosis and vision changes were the cheek, the nose, and the nasolabial fold. The cheek was the most common site associated with stroke. “These findings are similar to those of previous studies, further emphasizing that the nose, nasolabial fold, and cheek are possibly challenging injection sites,” she said.

“In general, as the face is a highly vascular area with many anastomoses, it’s especially important to be aware of facial anatomy when injecting. In addition to awareness of anatomy, injection techniques can influence vascular complications. Unfortunately, the event narratives in the MAUDE database did not go into detail about the procedural technique.”

Ms. Xiong said that as the popularity of dermal fillers continues to grow, “it’s important for providers to understand the possible adverse events, both to better counsel patients and to improve safety management. The proportion of serious complications such as vascular necrosis and vision changes have increased from 2014 to 2020. This highlights an increased need for training to better understand facial anatomy and to emphasize practice techniques to minimize risk.”

Dr. Lee acknowledged certain limitations of the study, including that “submission of adverse events to the MAUDE database are not verified or standardized,” she told this news organization.

“With the ever-increasing popularity of fillers, it is not surprising that the absolute number of complications is rising, but it is also reassuring to see that the overall ratio of complications per hundred reports is down,” said Lawrence J. Green, MD, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study. “I would be curious to know what proportion of filler complications are due to non–core practitioners compared to dermatologists and plastic surgeons.”

The researchers reported having no financial disclosures.

Dr. Green disclosed that he is a speaker, consultant, or investigator for numerous pharmaceutical companies.

dbrunk@mdedge.com

The number of adverse events involving vascular necrosis and vision changes following injection of dermal fillers increased from 2014 to 2020, results from a large database analysis showed.

“The ASDS estimates that 1.6 million soft tissue filler procedures were performed in 2019, a 78% increase from 2012,” presenting author Michelle Xiong, a 4th-year student at Brown University, Providence, R.I., said during a virtual abstract session at the annual meeting of the American Society for Dermatologic Surgery. “The popularity of dermal fillers continues to increase. With that, there is increasing concern of possible associated adverse events. Most concerning are those related to vascular occlusion.”

Under the supervision of senior author Kachiu C. Lee, MD, MPH, of Main Line Center for Laser Surgery in Ardmore, Pa., Ms. Xiong and colleagues analyzed the Food and Drug Administration’s Manufacturer and User Facility Device Experience (MAUDE) database of medical device–related adverse event reports, to better understand and characterize dermal filler-related complications. They limited the analysis to adverse events involving injectable fillers from January 2014 to December 2020 and determined the number of complications by type per year and reviewed reports to identify injection site locations. Next, they used the binomial test to compare the proportion of complication categories from 2014 through 2016 and from 2017 through 2020.

In all, 5,994 reports were identified during the 7-year study period. To evaluate trends over time, the researchers estimated the rate of complications per 100 reports each year. While the absolute number of reports increased over time, the rate of adverse events per 100 reports decreased, suggesting an overall improvement in safety.

When the researchers focused on complications involving vascular occlusion, they found that vascular necrosis accounted for 3.5% of all complications, compared with vision changes (1.5% of all complications), and stroke (0.3% of all complications). When comparing the years 2014-2016 with 2017-2020, there was a significant increase in adverse events involving vascular necrosis (0.9%; P = .018) and vision changes (0.94%; P = .001), but no significant difference in the number of reports of stroke (-0.1%; P = .409). “This highlights that serious complications like necrosis and vision changes have increased over time,” Ms. Xiong said.

Overall, the three most common injection sites involving necrosis and vision changes were the cheek, the nose, and the nasolabial fold. The cheek was the most common site associated with stroke. “These findings are similar to those of previous studies, further emphasizing that the nose, nasolabial fold, and cheek are possibly challenging injection sites,” she said.

“In general, as the face is a highly vascular area with many anastomoses, it’s especially important to be aware of facial anatomy when injecting. In addition to awareness of anatomy, injection techniques can influence vascular complications. Unfortunately, the event narratives in the MAUDE database did not go into detail about the procedural technique.”

Ms. Xiong said that as the popularity of dermal fillers continues to grow, “it’s important for providers to understand the possible adverse events, both to better counsel patients and to improve safety management. The proportion of serious complications such as vascular necrosis and vision changes have increased from 2014 to 2020. This highlights an increased need for training to better understand facial anatomy and to emphasize practice techniques to minimize risk.”

Dr. Lee acknowledged certain limitations of the study, including that “submission of adverse events to the MAUDE database are not verified or standardized,” she told this news organization.

“With the ever-increasing popularity of fillers, it is not surprising that the absolute number of complications is rising, but it is also reassuring to see that the overall ratio of complications per hundred reports is down,” said Lawrence J. Green, MD, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study. “I would be curious to know what proportion of filler complications are due to non–core practitioners compared to dermatologists and plastic surgeons.”

The researchers reported having no financial disclosures.

Dr. Green disclosed that he is a speaker, consultant, or investigator for numerous pharmaceutical companies.

dbrunk@mdedge.com

The number of adverse events involving vascular necrosis and vision changes following injection of dermal fillers increased from 2014 to 2020, results from a large database analysis showed.

“The ASDS estimates that 1.6 million soft tissue filler procedures were performed in 2019, a 78% increase from 2012,” presenting author Michelle Xiong, a 4th-year student at Brown University, Providence, R.I., said during a virtual abstract session at the annual meeting of the American Society for Dermatologic Surgery. “The popularity of dermal fillers continues to increase. With that, there is increasing concern of possible associated adverse events. Most concerning are those related to vascular occlusion.”

Under the supervision of senior author Kachiu C. Lee, MD, MPH, of Main Line Center for Laser Surgery in Ardmore, Pa., Ms. Xiong and colleagues analyzed the Food and Drug Administration’s Manufacturer and User Facility Device Experience (MAUDE) database of medical device–related adverse event reports, to better understand and characterize dermal filler-related complications. They limited the analysis to adverse events involving injectable fillers from January 2014 to December 2020 and determined the number of complications by type per year and reviewed reports to identify injection site locations. Next, they used the binomial test to compare the proportion of complication categories from 2014 through 2016 and from 2017 through 2020.

In all, 5,994 reports were identified during the 7-year study period. To evaluate trends over time, the researchers estimated the rate of complications per 100 reports each year. While the absolute number of reports increased over time, the rate of adverse events per 100 reports decreased, suggesting an overall improvement in safety.

When the researchers focused on complications involving vascular occlusion, they found that vascular necrosis accounted for 3.5% of all complications, compared with vision changes (1.5% of all complications), and stroke (0.3% of all complications). When comparing the years 2014-2016 with 2017-2020, there was a significant increase in adverse events involving vascular necrosis (0.9%; P = .018) and vision changes (0.94%; P = .001), but no significant difference in the number of reports of stroke (-0.1%; P = .409). “This highlights that serious complications like necrosis and vision changes have increased over time,” Ms. Xiong said.

Overall, the three most common injection sites involving necrosis and vision changes were the cheek, the nose, and the nasolabial fold. The cheek was the most common site associated with stroke. “These findings are similar to those of previous studies, further emphasizing that the nose, nasolabial fold, and cheek are possibly challenging injection sites,” she said.

“In general, as the face is a highly vascular area with many anastomoses, it’s especially important to be aware of facial anatomy when injecting. In addition to awareness of anatomy, injection techniques can influence vascular complications. Unfortunately, the event narratives in the MAUDE database did not go into detail about the procedural technique.”

Ms. Xiong said that as the popularity of dermal fillers continues to grow, “it’s important for providers to understand the possible adverse events, both to better counsel patients and to improve safety management. The proportion of serious complications such as vascular necrosis and vision changes have increased from 2014 to 2020. This highlights an increased need for training to better understand facial anatomy and to emphasize practice techniques to minimize risk.”

Dr. Lee acknowledged certain limitations of the study, including that “submission of adverse events to the MAUDE database are not verified or standardized,” she told this news organization.

“With the ever-increasing popularity of fillers, it is not surprising that the absolute number of complications is rising, but it is also reassuring to see that the overall ratio of complications per hundred reports is down,” said Lawrence J. Green, MD, clinical professor of dermatology at George Washington University, Washington, who was asked to comment on the study. “I would be curious to know what proportion of filler complications are due to non–core practitioners compared to dermatologists and plastic surgeons.”

The researchers reported having no financial disclosures.

Dr. Green disclosed that he is a speaker, consultant, or investigator for numerous pharmaceutical companies.

dbrunk@mdedge.com

Adolescents with psychogenic nonepileptic seizures (PNES) experience severe bullying by fellow students and school staff alike, results of a small study suggest.

The school experience of teens with PNES is overwhelmingly negative, study investigator Andrea Tanner, PhD, a postdoctoral fellow at Indiana University School of Nursing, Indianapolis.

She hopes this research will spur a collaborative effort between students, schools, families, and health care providers “to develop an effective plan to help these adolescents cope, to manage this condition, and hopefully reach seizure freedom.”

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Anxiety, perfectionism

Although psychogenic seizures resemble epileptic seizures, they have a psychological basis and, unlike epilepsy, are not caused by abnormal electrical brain activity.

While the school experience has previously been identified as a source of predisposing, precipitating, and perpetuating factors for PNES, little is known about the school experience of adolescents with the disorder and the role it may play in PNES management, the investigators noted.

During her 20 years as a school nurse, Dr. Tanner saw firsthand how school staff struggled with responding appropriately to teens with PNES. “They wanted to call 911 every time; they wanted to respond as if it [were] an epileptic seizure.”

For the study, she interviewed 10 teens with PNES, aged 12 to 19 years, whom she found mostly through Facebook support groups but also through flyers. All participants had undergone video EEG and been diagnosed with PNES.

From the interviews, Dr. Tanner and colleagues conducted a qualitative content analysis and uncovered “overarching” themes.

A main theme was stress, some of which focused on bullying by peers or harassment by school personnel, much of which was related to accusations of the children “faking” seizures to get attention, said Dr. Tanner.

Some teens reported being banned from school events, such as field trips, out of concern they would be a “distraction,” which led to feelings of isolation and exclusion, said Dr. Tanner.

Research points to a growing incidence of PNES among adolescents. This may be because it is now better recognized, or it may stem from the unique stressors today’s teens face, said Dr. Tanner.

Adolescents discussed the pressures they feel to be the best at everything. “They wanted to be good in athletics; they wanted to be good in academics; they wanted to get into a good college,” said Dr. Tanner.

Some study participants had undergone psychotherapy, including cognitive-behavioral therapy, and others had investigated mindfulness-based therapy. However, not all were receiving treatment. For some, such care was inaccessible, while others had tried a mental health care intervention but had abandoned it.

Although all the study participants were female, Dr. Tanner has interviewed males outside this study and found their experiences are similar.

Her next research step is to try to quantify the findings. “I would like to begin to look at what would be the appropriate outcomes if I were to do an intervention to improve the school experience.”

Her message for doctors is to see school nurses as a “partner” or “liaison” who “can bridge the world of health care and education.”
 

Important, novel research

Commenting on the research, Barbara Dworetzky, MD, Chief, Epilepsy, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, said it’s “important and novel.”

The study focuses on the main factors – or themes – that lead to increased stress, such as bullying, isolation, and “not being believed,” that are likely triggers for PNES, said Dr. Dworetzky.

The study is also important because it focuses on factors that help make the girls “feel supported and protected” – for example, having staff “take the episodes seriously,” she said.

The study’s qualitative measures “are a valid way of understanding these girls and giving them a voice,” said Dr. Dworetzky. She added the study provides “practical information” that could help target treatments to improve outcomes in this group.

A limitation of the study was that the very small cohort of teenage girls was selected only through families in Facebook support groups or flyers to school nurses, said Dr. Dworetzky.

“There are likely many other groups who don’t even have families trying to help them. Larger cohorts without this type of bias may be next steps.”

A version of this article first appeared on Medscape.com.

Adolescents with psychogenic nonepileptic seizures (PNES) experience severe bullying by fellow students and school staff alike, results of a small study suggest.

The school experience of teens with PNES is overwhelmingly negative, study investigator Andrea Tanner, PhD, a postdoctoral fellow at Indiana University School of Nursing, Indianapolis.

She hopes this research will spur a collaborative effort between students, schools, families, and health care providers “to develop an effective plan to help these adolescents cope, to manage this condition, and hopefully reach seizure freedom.”

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Anxiety, perfectionism

Although psychogenic seizures resemble epileptic seizures, they have a psychological basis and, unlike epilepsy, are not caused by abnormal electrical brain activity.

While the school experience has previously been identified as a source of predisposing, precipitating, and perpetuating factors for PNES, little is known about the school experience of adolescents with the disorder and the role it may play in PNES management, the investigators noted.

During her 20 years as a school nurse, Dr. Tanner saw firsthand how school staff struggled with responding appropriately to teens with PNES. “They wanted to call 911 every time; they wanted to respond as if it [were] an epileptic seizure.”

For the study, she interviewed 10 teens with PNES, aged 12 to 19 years, whom she found mostly through Facebook support groups but also through flyers. All participants had undergone video EEG and been diagnosed with PNES.

From the interviews, Dr. Tanner and colleagues conducted a qualitative content analysis and uncovered “overarching” themes.

A main theme was stress, some of which focused on bullying by peers or harassment by school personnel, much of which was related to accusations of the children “faking” seizures to get attention, said Dr. Tanner.

Some teens reported being banned from school events, such as field trips, out of concern they would be a “distraction,” which led to feelings of isolation and exclusion, said Dr. Tanner.

Research points to a growing incidence of PNES among adolescents. This may be because it is now better recognized, or it may stem from the unique stressors today’s teens face, said Dr. Tanner.

Adolescents discussed the pressures they feel to be the best at everything. “They wanted to be good in athletics; they wanted to be good in academics; they wanted to get into a good college,” said Dr. Tanner.

Some study participants had undergone psychotherapy, including cognitive-behavioral therapy, and others had investigated mindfulness-based therapy. However, not all were receiving treatment. For some, such care was inaccessible, while others had tried a mental health care intervention but had abandoned it.

Although all the study participants were female, Dr. Tanner has interviewed males outside this study and found their experiences are similar.

Her next research step is to try to quantify the findings. “I would like to begin to look at what would be the appropriate outcomes if I were to do an intervention to improve the school experience.”

Her message for doctors is to see school nurses as a “partner” or “liaison” who “can bridge the world of health care and education.”
 

Important, novel research

Commenting on the research, Barbara Dworetzky, MD, Chief, Epilepsy, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, said it’s “important and novel.”

The study focuses on the main factors – or themes – that lead to increased stress, such as bullying, isolation, and “not being believed,” that are likely triggers for PNES, said Dr. Dworetzky.

The study is also important because it focuses on factors that help make the girls “feel supported and protected” – for example, having staff “take the episodes seriously,” she said.

The study’s qualitative measures “are a valid way of understanding these girls and giving them a voice,” said Dr. Dworetzky. She added the study provides “practical information” that could help target treatments to improve outcomes in this group.

A limitation of the study was that the very small cohort of teenage girls was selected only through families in Facebook support groups or flyers to school nurses, said Dr. Dworetzky.

“There are likely many other groups who don’t even have families trying to help them. Larger cohorts without this type of bias may be next steps.”

A version of this article first appeared on Medscape.com.

Adolescents with psychogenic nonepileptic seizures (PNES) experience severe bullying by fellow students and school staff alike, results of a small study suggest.

The school experience of teens with PNES is overwhelmingly negative, study investigator Andrea Tanner, PhD, a postdoctoral fellow at Indiana University School of Nursing, Indianapolis.

She hopes this research will spur a collaborative effort between students, schools, families, and health care providers “to develop an effective plan to help these adolescents cope, to manage this condition, and hopefully reach seizure freedom.”

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Anxiety, perfectionism

Although psychogenic seizures resemble epileptic seizures, they have a psychological basis and, unlike epilepsy, are not caused by abnormal electrical brain activity.

While the school experience has previously been identified as a source of predisposing, precipitating, and perpetuating factors for PNES, little is known about the school experience of adolescents with the disorder and the role it may play in PNES management, the investigators noted.

During her 20 years as a school nurse, Dr. Tanner saw firsthand how school staff struggled with responding appropriately to teens with PNES. “They wanted to call 911 every time; they wanted to respond as if it [were] an epileptic seizure.”

For the study, she interviewed 10 teens with PNES, aged 12 to 19 years, whom she found mostly through Facebook support groups but also through flyers. All participants had undergone video EEG and been diagnosed with PNES.

From the interviews, Dr. Tanner and colleagues conducted a qualitative content analysis and uncovered “overarching” themes.

A main theme was stress, some of which focused on bullying by peers or harassment by school personnel, much of which was related to accusations of the children “faking” seizures to get attention, said Dr. Tanner.

Some teens reported being banned from school events, such as field trips, out of concern they would be a “distraction,” which led to feelings of isolation and exclusion, said Dr. Tanner.

Research points to a growing incidence of PNES among adolescents. This may be because it is now better recognized, or it may stem from the unique stressors today’s teens face, said Dr. Tanner.

Adolescents discussed the pressures they feel to be the best at everything. “They wanted to be good in athletics; they wanted to be good in academics; they wanted to get into a good college,” said Dr. Tanner.

Some study participants had undergone psychotherapy, including cognitive-behavioral therapy, and others had investigated mindfulness-based therapy. However, not all were receiving treatment. For some, such care was inaccessible, while others had tried a mental health care intervention but had abandoned it.

Although all the study participants were female, Dr. Tanner has interviewed males outside this study and found their experiences are similar.

Her next research step is to try to quantify the findings. “I would like to begin to look at what would be the appropriate outcomes if I were to do an intervention to improve the school experience.”

Her message for doctors is to see school nurses as a “partner” or “liaison” who “can bridge the world of health care and education.”
 

Important, novel research

Commenting on the research, Barbara Dworetzky, MD, Chief, Epilepsy, Brigham and Women’s Hospital, and professor of neurology, Harvard Medical School, said it’s “important and novel.”

The study focuses on the main factors – or themes – that lead to increased stress, such as bullying, isolation, and “not being believed,” that are likely triggers for PNES, said Dr. Dworetzky.

The study is also important because it focuses on factors that help make the girls “feel supported and protected” – for example, having staff “take the episodes seriously,” she said.

The study’s qualitative measures “are a valid way of understanding these girls and giving them a voice,” said Dr. Dworetzky. She added the study provides “practical information” that could help target treatments to improve outcomes in this group.

A limitation of the study was that the very small cohort of teenage girls was selected only through families in Facebook support groups or flyers to school nurses, said Dr. Dworetzky.

“There are likely many other groups who don’t even have families trying to help them. Larger cohorts without this type of bias may be next steps.”

A version of this article first appeared on Medscape.com.

Women with epilepsy are more than twice as likely as those without the disorder to report physical, sexual, or emotional abuse during pregnancy, new research shows.

Study investigator Naveed Chaudhry, MD, a recent epilepsy fellow and assistant professor of neurology, University of Colorado School of Medicine, described the finding as “alarming” and called for more support for this patient population.

Investigators found that women with epilepsy are also more likely to report other stressors, including divorce, illness, lost pay, and partner discord, while expecting.

“As epilepsy physicians, it’s important that we ask the right questions and dive a little bit deeper with these patients, even if it’s uncomfortable and not something we’re used to,” said Dr. Chaudhry.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Cause for concern

Women with epilepsy may be under stress for a variety of social and economic reasons. In some women, stress can trigger seizures, and during pregnancy, this can lead to complications such as preterm labor and low birth weight.

For the study, researchers tapped into the Center for Disease Control and Prevention Pregnancy Risk Assessment and Monitoring System (PRAMS). This database includes information from surveys asking women across the U.S. about their pregnancy and postpartum period.

Thirteen states collected data on stresses in women with and without epilepsy. Respondents were asked about 14 economic and other worries in the year prior to their baby’s birth, including the pregnancy period.

The analysis included 64,951 women, 1,140 of whom had epilepsy, who were included in surveys from 2012-2020. There were no significant demographic differences between those with and those without the disorder.

After adjusting for maternal age, race, ethnicity, marital status, education, and socioeconomic status, the study found that women with epilepsy experienced an average of 2.41 of the stressors compared with 1.72 for women without epilepsy.

Women with epilepsy were more likely to have experienced family illness, divorce, homelessness, partner job loss, reduced work or pay, increased arguments, having a partner in jail, drug use, and the death of someone close to them.

The results showed that unmarried and younger women as well as those with lower incomes were particularly prone to experience stress during pregnancy.

It’s not clear why women with epilepsy report more stressors. “Looking at the literature, no one has really looked at the exact reason for this, but we postulate it could be a lack of supports and support systems,” said Dr. Chaudhry.

Women were asked about physical, sexual, and emotional abuse. Results showed that substantially more women with epilepsy than those without the disorder reported such abuse during pregnancy – 10.6% versus 4.1%. The adjusted odds ratio for women with epilepsy reporting abuse was 2.78 (95% CI, 2.07-3.74).

“That raises our concern and needs to be looked at in more detail,” said Dr. Chaudhry.

It is unclear whether some women might have had psychogenic non-epileptic seizures (PNES), which are linked to a higher rate of abuse, said Dr. Chaudhry. “But the prevalence of PNES in the general population is quite low, so we don’t think it’s contributing to a large extent to this finding.”

The findings highlight the importance of addressing stress in women with epilepsy during pregnancy, he said. “We need to have good support services and we need to counsel women to optimize good outcomes.”

This applies to all women of childbearing age. “We suspect abuse and stressors are going to be going on throughout that period,” said Dr. Chaudhry. “It’s important to ask about it and have appropriate support staff and social work and people available to help when an issue is identified.”
 

Stress a common seizure trigger

Commenting on the research, Kimford Meador, MD, professor, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, noted the study was well conducted and had a large sample size.

The findings are important, as stress is a common trigger for seizures in people with epilepsy and is associated with mood and anxiety, which can affect quality of life, said Dr. Meador.

Results of his analysis from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, also presented at this year’s AES meeting, showed that women with epilepsy had more depressive symptoms during the postpartum period and more anxiety symptoms during pregnancy and postpartum in comparison with those without epilepsy.

Dr. Meador’s group also recently conducted a study that was published in JAMA Neurology, showing that in women with epilepsy during the postpartum period, anxiety is associated with lower cognitive ability in their children at age 2 years.

“All these findings highlight the importance of assessing and managing stress, anxiety, and mood in women with epilepsy,” said Dr. Meador. “Interventions could impact seizures and quality of life in pregnant women with epilepsy and long-term outcomes in their children.”

A version of this article first appeared on Medscape.com.

Women with epilepsy are more than twice as likely as those without the disorder to report physical, sexual, or emotional abuse during pregnancy, new research shows.

Study investigator Naveed Chaudhry, MD, a recent epilepsy fellow and assistant professor of neurology, University of Colorado School of Medicine, described the finding as “alarming” and called for more support for this patient population.

Investigators found that women with epilepsy are also more likely to report other stressors, including divorce, illness, lost pay, and partner discord, while expecting.

“As epilepsy physicians, it’s important that we ask the right questions and dive a little bit deeper with these patients, even if it’s uncomfortable and not something we’re used to,” said Dr. Chaudhry.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Cause for concern

Women with epilepsy may be under stress for a variety of social and economic reasons. In some women, stress can trigger seizures, and during pregnancy, this can lead to complications such as preterm labor and low birth weight.

For the study, researchers tapped into the Center for Disease Control and Prevention Pregnancy Risk Assessment and Monitoring System (PRAMS). This database includes information from surveys asking women across the U.S. about their pregnancy and postpartum period.

Thirteen states collected data on stresses in women with and without epilepsy. Respondents were asked about 14 economic and other worries in the year prior to their baby’s birth, including the pregnancy period.

The analysis included 64,951 women, 1,140 of whom had epilepsy, who were included in surveys from 2012-2020. There were no significant demographic differences between those with and those without the disorder.

After adjusting for maternal age, race, ethnicity, marital status, education, and socioeconomic status, the study found that women with epilepsy experienced an average of 2.41 of the stressors compared with 1.72 for women without epilepsy.

Women with epilepsy were more likely to have experienced family illness, divorce, homelessness, partner job loss, reduced work or pay, increased arguments, having a partner in jail, drug use, and the death of someone close to them.

The results showed that unmarried and younger women as well as those with lower incomes were particularly prone to experience stress during pregnancy.

It’s not clear why women with epilepsy report more stressors. “Looking at the literature, no one has really looked at the exact reason for this, but we postulate it could be a lack of supports and support systems,” said Dr. Chaudhry.

Women were asked about physical, sexual, and emotional abuse. Results showed that substantially more women with epilepsy than those without the disorder reported such abuse during pregnancy – 10.6% versus 4.1%. The adjusted odds ratio for women with epilepsy reporting abuse was 2.78 (95% CI, 2.07-3.74).

“That raises our concern and needs to be looked at in more detail,” said Dr. Chaudhry.

It is unclear whether some women might have had psychogenic non-epileptic seizures (PNES), which are linked to a higher rate of abuse, said Dr. Chaudhry. “But the prevalence of PNES in the general population is quite low, so we don’t think it’s contributing to a large extent to this finding.”

The findings highlight the importance of addressing stress in women with epilepsy during pregnancy, he said. “We need to have good support services and we need to counsel women to optimize good outcomes.”

This applies to all women of childbearing age. “We suspect abuse and stressors are going to be going on throughout that period,” said Dr. Chaudhry. “It’s important to ask about it and have appropriate support staff and social work and people available to help when an issue is identified.”
 

Stress a common seizure trigger

Commenting on the research, Kimford Meador, MD, professor, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, noted the study was well conducted and had a large sample size.

The findings are important, as stress is a common trigger for seizures in people with epilepsy and is associated with mood and anxiety, which can affect quality of life, said Dr. Meador.

Results of his analysis from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, also presented at this year’s AES meeting, showed that women with epilepsy had more depressive symptoms during the postpartum period and more anxiety symptoms during pregnancy and postpartum in comparison with those without epilepsy.

Dr. Meador’s group also recently conducted a study that was published in JAMA Neurology, showing that in women with epilepsy during the postpartum period, anxiety is associated with lower cognitive ability in their children at age 2 years.

“All these findings highlight the importance of assessing and managing stress, anxiety, and mood in women with epilepsy,” said Dr. Meador. “Interventions could impact seizures and quality of life in pregnant women with epilepsy and long-term outcomes in their children.”

A version of this article first appeared on Medscape.com.

Women with epilepsy are more than twice as likely as those without the disorder to report physical, sexual, or emotional abuse during pregnancy, new research shows.

Study investigator Naveed Chaudhry, MD, a recent epilepsy fellow and assistant professor of neurology, University of Colorado School of Medicine, described the finding as “alarming” and called for more support for this patient population.

Investigators found that women with epilepsy are also more likely to report other stressors, including divorce, illness, lost pay, and partner discord, while expecting.

“As epilepsy physicians, it’s important that we ask the right questions and dive a little bit deeper with these patients, even if it’s uncomfortable and not something we’re used to,” said Dr. Chaudhry.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

Cause for concern

Women with epilepsy may be under stress for a variety of social and economic reasons. In some women, stress can trigger seizures, and during pregnancy, this can lead to complications such as preterm labor and low birth weight.

For the study, researchers tapped into the Center for Disease Control and Prevention Pregnancy Risk Assessment and Monitoring System (PRAMS). This database includes information from surveys asking women across the U.S. about their pregnancy and postpartum period.

Thirteen states collected data on stresses in women with and without epilepsy. Respondents were asked about 14 economic and other worries in the year prior to their baby’s birth, including the pregnancy period.

The analysis included 64,951 women, 1,140 of whom had epilepsy, who were included in surveys from 2012-2020. There were no significant demographic differences between those with and those without the disorder.

After adjusting for maternal age, race, ethnicity, marital status, education, and socioeconomic status, the study found that women with epilepsy experienced an average of 2.41 of the stressors compared with 1.72 for women without epilepsy.

Women with epilepsy were more likely to have experienced family illness, divorce, homelessness, partner job loss, reduced work or pay, increased arguments, having a partner in jail, drug use, and the death of someone close to them.

The results showed that unmarried and younger women as well as those with lower incomes were particularly prone to experience stress during pregnancy.

It’s not clear why women with epilepsy report more stressors. “Looking at the literature, no one has really looked at the exact reason for this, but we postulate it could be a lack of supports and support systems,” said Dr. Chaudhry.

Women were asked about physical, sexual, and emotional abuse. Results showed that substantially more women with epilepsy than those without the disorder reported such abuse during pregnancy – 10.6% versus 4.1%. The adjusted odds ratio for women with epilepsy reporting abuse was 2.78 (95% CI, 2.07-3.74).

“That raises our concern and needs to be looked at in more detail,” said Dr. Chaudhry.

It is unclear whether some women might have had psychogenic non-epileptic seizures (PNES), which are linked to a higher rate of abuse, said Dr. Chaudhry. “But the prevalence of PNES in the general population is quite low, so we don’t think it’s contributing to a large extent to this finding.”

The findings highlight the importance of addressing stress in women with epilepsy during pregnancy, he said. “We need to have good support services and we need to counsel women to optimize good outcomes.”

This applies to all women of childbearing age. “We suspect abuse and stressors are going to be going on throughout that period,” said Dr. Chaudhry. “It’s important to ask about it and have appropriate support staff and social work and people available to help when an issue is identified.”
 

Stress a common seizure trigger

Commenting on the research, Kimford Meador, MD, professor, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, noted the study was well conducted and had a large sample size.

The findings are important, as stress is a common trigger for seizures in people with epilepsy and is associated with mood and anxiety, which can affect quality of life, said Dr. Meador.

Results of his analysis from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, also presented at this year’s AES meeting, showed that women with epilepsy had more depressive symptoms during the postpartum period and more anxiety symptoms during pregnancy and postpartum in comparison with those without epilepsy.

Dr. Meador’s group also recently conducted a study that was published in JAMA Neurology, showing that in women with epilepsy during the postpartum period, anxiety is associated with lower cognitive ability in their children at age 2 years.

“All these findings highlight the importance of assessing and managing stress, anxiety, and mood in women with epilepsy,” said Dr. Meador. “Interventions could impact seizures and quality of life in pregnant women with epilepsy and long-term outcomes in their children.”

A version of this article first appeared on Medscape.com.

In addition to high rates of anxiety and mood disorders, epilepsy is associated with several comorbidities, including headache, hypertension, and back pain, new research shows. Investigators also found racial and ethnic disparities in comorbidity prevalence.

“Our study identified that people with epilepsy have complex health care needs that extend well beyond their epilepsy,” said co-investigator Wyatt P. Bensken, a PhD candidate in the Department of Population and Quantitative Health Sciences at Case Western Reserve University, Cleveland.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

A vulnerable population

Researchers identified individuals with epilepsy using Medicaid claims from 2010 to 2014. Mr. Bensken noted that the approximately one-third of patients with epilepsy covered by Medicaid represent “the most vulnerable” population with the disorder because they may not be working and often have other disabilities.

Based on an algorithm that puts diagnostic codes into clinically meaningful categories, the investigators focused on 190 conditions.

“A strength of the study was that we were able to cast such a broad net” to capture conditions, Mr. Bensken said.

Anxiety and mood disorders were originally in separate categories but were grouped together “after recognizing that those who had one pretty much had the other,” he added.

The researchers used a machine learning technique known as association rule mining (ARM) to uncover frequently occurring conditions and combinations of conditions. This same statistical technique is used by companies such as Amazon to determine future purchases based on articles people have bought.

Among 81,963 patients with epilepsy, the most common conditions were anxiety and mood disorders (46.5%). These were followed by hypertension (36.9%), back problems (35.2%), developmental disorders (31.6%), and headache including migraine (29.5%). Urinary tract infections (UTIs) were experienced by 22.8% of the sample.

The rate of anxiety and mood disorders was not unexpected, “but I was surprised to see hypertension so high on the list,” said Mr. Bensken. He noted there is also increasing evidence pointing to a cardiovascular-epilepsy connection.
 

What should neurologists do?

The study also highlights the relatively high rate of back problems, which are not usually considered a comorbidity in patients with epilepsy, Mr. Bensken said. “Back problems likely greatly impact a patient’s quality of life, and seeing them so high on the list makes me wonder if neurologists or epileptologists or primary care doctors are even asking about back pain and how that might impact the ability to function day to day,” he added.

How do these rates compare with the general population? From other studies, the estimated prevalence for anxiety and mood disorders is 20%-30%, compared with almost 50% of the current sample, said Mr. Bensken.

In addition, the rate of hypertension in the study’s epilepsy population was about 7% higher than the general population, and the rate of UTIs was about 12% higher, he reported.

When examining combinations of conditions, anxiety and mood disorders continued to have an “outsized” prevalence, appearing in nearly every combination, the investigators noted.

Almost a quarter (24.7%) of participants had back problems plus anxiety and a mood disorder, and about 15% had headaches and back problems as well as anxiety and a mood disorder.

“That’s a non-negligible amount of the population that have not just one or two things going on but three and four,” said Mr. Bensken.

These new results underscore how complex these patients can be and the need to integrate medical care among different specialties, he noted.

“We don’t believe it’s the neurologist’s job to also manage the hypertension, but being aware of how prevalent hypertension may be and working with the primary care doctor, or at least checking in with the patient and asking if they’re managing their hypertension, is a real priority,” he said.

Researchers also used the ARM system to identify racial disparities, “which have been largely understudied in the epilepsy context,” said Mr. Bensken.

American Indians and Alaskan Natives had a substantially higher prevalence of developmental disabilities, while Black participants had a higher prevalence of hypertension.

One of the study’s themes was that disparities were not uniform, Mr. Bensken noted. “It wasn’t that in every condition the prevalence was lowest for White individuals and highest for everybody else,” he said.

These results point to the need for a larger study to examine the cultural context of these subgroups and such things as structural racism that might drive disparities, he added.

When researchers examined combinations of comorbidities in individuals in the top quartile of hospitalizations and emergency department visits, they found high users had a much higher disease burden, with 75.8% having anxiety or a mood disorder.

The study highlights that patients with epilepsy on Medicaid are “a high priority population,” said Mr. Bensken.
 

‘Drift down hypothesis’

Commenting on the findings, Fred A. Lado, MD, PhD, director of epilepsy at Northwell Health Eastern and Central Regions, said the increased incidence of comorbidities in patients of low socioeconomic status was not surprising.

“The interesting data here is that we see an even higher incidence among people with epilepsy,” said Dr. Lado, who was not involved with the research.

The study shows how epilepsy exacerbates the effects of low socioeconomic status, he added.

“One of the determinants of socioeconomic status in this case may well be the fact they have seizures and have a limited ability to work and are often more dependent on state assistance and disability support,” Dr. Lado said.

He also referred to the “drift down hypothesis” of chronic disease. “If you have epilepsy and are born into a middle-class family, chances are you will be on disability and can’t work, so you probably have a lower socioeconomic status than your family did as you grew up.”

Dr. Lado noted how “extremely common” mood disorders are in this population and that certain pain syndromes “tracked with those mood disorders.”

“We know mood disorders are more prevalent in people with epilepsy, and now we see that pain-related problems – headache and back pain – are more prevalent in people with epilepsy,” he said.

The data showing “downstream effects of the mood disorders,” from epilepsy to mood disorders to pain disorders, was “very interesting,” Dr. Lado said.

The study was funded by the Centers for Disease Control and Prevention and the National Institute on Minority Health and Health Disparities of the National Institutes of Health. Mr. Bensken has reported receiving research support for this work from the NIH.

A version of this article first appeared on Medscape.com.

In addition to high rates of anxiety and mood disorders, epilepsy is associated with several comorbidities, including headache, hypertension, and back pain, new research shows. Investigators also found racial and ethnic disparities in comorbidity prevalence.

“Our study identified that people with epilepsy have complex health care needs that extend well beyond their epilepsy,” said co-investigator Wyatt P. Bensken, a PhD candidate in the Department of Population and Quantitative Health Sciences at Case Western Reserve University, Cleveland.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

A vulnerable population

Researchers identified individuals with epilepsy using Medicaid claims from 2010 to 2014. Mr. Bensken noted that the approximately one-third of patients with epilepsy covered by Medicaid represent “the most vulnerable” population with the disorder because they may not be working and often have other disabilities.

Based on an algorithm that puts diagnostic codes into clinically meaningful categories, the investigators focused on 190 conditions.

“A strength of the study was that we were able to cast such a broad net” to capture conditions, Mr. Bensken said.

Anxiety and mood disorders were originally in separate categories but were grouped together “after recognizing that those who had one pretty much had the other,” he added.

The researchers used a machine learning technique known as association rule mining (ARM) to uncover frequently occurring conditions and combinations of conditions. This same statistical technique is used by companies such as Amazon to determine future purchases based on articles people have bought.

Among 81,963 patients with epilepsy, the most common conditions were anxiety and mood disorders (46.5%). These were followed by hypertension (36.9%), back problems (35.2%), developmental disorders (31.6%), and headache including migraine (29.5%). Urinary tract infections (UTIs) were experienced by 22.8% of the sample.

The rate of anxiety and mood disorders was not unexpected, “but I was surprised to see hypertension so high on the list,” said Mr. Bensken. He noted there is also increasing evidence pointing to a cardiovascular-epilepsy connection.
 

What should neurologists do?

The study also highlights the relatively high rate of back problems, which are not usually considered a comorbidity in patients with epilepsy, Mr. Bensken said. “Back problems likely greatly impact a patient’s quality of life, and seeing them so high on the list makes me wonder if neurologists or epileptologists or primary care doctors are even asking about back pain and how that might impact the ability to function day to day,” he added.

How do these rates compare with the general population? From other studies, the estimated prevalence for anxiety and mood disorders is 20%-30%, compared with almost 50% of the current sample, said Mr. Bensken.

In addition, the rate of hypertension in the study’s epilepsy population was about 7% higher than the general population, and the rate of UTIs was about 12% higher, he reported.

When examining combinations of conditions, anxiety and mood disorders continued to have an “outsized” prevalence, appearing in nearly every combination, the investigators noted.

Almost a quarter (24.7%) of participants had back problems plus anxiety and a mood disorder, and about 15% had headaches and back problems as well as anxiety and a mood disorder.

“That’s a non-negligible amount of the population that have not just one or two things going on but three and four,” said Mr. Bensken.

These new results underscore how complex these patients can be and the need to integrate medical care among different specialties, he noted.

“We don’t believe it’s the neurologist’s job to also manage the hypertension, but being aware of how prevalent hypertension may be and working with the primary care doctor, or at least checking in with the patient and asking if they’re managing their hypertension, is a real priority,” he said.

Researchers also used the ARM system to identify racial disparities, “which have been largely understudied in the epilepsy context,” said Mr. Bensken.

American Indians and Alaskan Natives had a substantially higher prevalence of developmental disabilities, while Black participants had a higher prevalence of hypertension.

One of the study’s themes was that disparities were not uniform, Mr. Bensken noted. “It wasn’t that in every condition the prevalence was lowest for White individuals and highest for everybody else,” he said.

These results point to the need for a larger study to examine the cultural context of these subgroups and such things as structural racism that might drive disparities, he added.

When researchers examined combinations of comorbidities in individuals in the top quartile of hospitalizations and emergency department visits, they found high users had a much higher disease burden, with 75.8% having anxiety or a mood disorder.

The study highlights that patients with epilepsy on Medicaid are “a high priority population,” said Mr. Bensken.
 

‘Drift down hypothesis’

Commenting on the findings, Fred A. Lado, MD, PhD, director of epilepsy at Northwell Health Eastern and Central Regions, said the increased incidence of comorbidities in patients of low socioeconomic status was not surprising.

“The interesting data here is that we see an even higher incidence among people with epilepsy,” said Dr. Lado, who was not involved with the research.

The study shows how epilepsy exacerbates the effects of low socioeconomic status, he added.

“One of the determinants of socioeconomic status in this case may well be the fact they have seizures and have a limited ability to work and are often more dependent on state assistance and disability support,” Dr. Lado said.

He also referred to the “drift down hypothesis” of chronic disease. “If you have epilepsy and are born into a middle-class family, chances are you will be on disability and can’t work, so you probably have a lower socioeconomic status than your family did as you grew up.”

Dr. Lado noted how “extremely common” mood disorders are in this population and that certain pain syndromes “tracked with those mood disorders.”

“We know mood disorders are more prevalent in people with epilepsy, and now we see that pain-related problems – headache and back pain – are more prevalent in people with epilepsy,” he said.

The data showing “downstream effects of the mood disorders,” from epilepsy to mood disorders to pain disorders, was “very interesting,” Dr. Lado said.

The study was funded by the Centers for Disease Control and Prevention and the National Institute on Minority Health and Health Disparities of the National Institutes of Health. Mr. Bensken has reported receiving research support for this work from the NIH.

A version of this article first appeared on Medscape.com.

In addition to high rates of anxiety and mood disorders, epilepsy is associated with several comorbidities, including headache, hypertension, and back pain, new research shows. Investigators also found racial and ethnic disparities in comorbidity prevalence.

“Our study identified that people with epilepsy have complex health care needs that extend well beyond their epilepsy,” said co-investigator Wyatt P. Bensken, a PhD candidate in the Department of Population and Quantitative Health Sciences at Case Western Reserve University, Cleveland.

The findings were presented at the annual meeting of the American Epilepsy Society.
 

A vulnerable population

Researchers identified individuals with epilepsy using Medicaid claims from 2010 to 2014. Mr. Bensken noted that the approximately one-third of patients with epilepsy covered by Medicaid represent “the most vulnerable” population with the disorder because they may not be working and often have other disabilities.

Based on an algorithm that puts diagnostic codes into clinically meaningful categories, the investigators focused on 190 conditions.

“A strength of the study was that we were able to cast such a broad net” to capture conditions, Mr. Bensken said.

Anxiety and mood disorders were originally in separate categories but were grouped together “after recognizing that those who had one pretty much had the other,” he added.

The researchers used a machine learning technique known as association rule mining (ARM) to uncover frequently occurring conditions and combinations of conditions. This same statistical technique is used by companies such as Amazon to determine future purchases based on articles people have bought.

Among 81,963 patients with epilepsy, the most common conditions were anxiety and mood disorders (46.5%). These were followed by hypertension (36.9%), back problems (35.2%), developmental disorders (31.6%), and headache including migraine (29.5%). Urinary tract infections (UTIs) were experienced by 22.8% of the sample.

The rate of anxiety and mood disorders was not unexpected, “but I was surprised to see hypertension so high on the list,” said Mr. Bensken. He noted there is also increasing evidence pointing to a cardiovascular-epilepsy connection.
 

What should neurologists do?

The study also highlights the relatively high rate of back problems, which are not usually considered a comorbidity in patients with epilepsy, Mr. Bensken said. “Back problems likely greatly impact a patient’s quality of life, and seeing them so high on the list makes me wonder if neurologists or epileptologists or primary care doctors are even asking about back pain and how that might impact the ability to function day to day,” he added.

How do these rates compare with the general population? From other studies, the estimated prevalence for anxiety and mood disorders is 20%-30%, compared with almost 50% of the current sample, said Mr. Bensken.

In addition, the rate of hypertension in the study’s epilepsy population was about 7% higher than the general population, and the rate of UTIs was about 12% higher, he reported.

When examining combinations of conditions, anxiety and mood disorders continued to have an “outsized” prevalence, appearing in nearly every combination, the investigators noted.

Almost a quarter (24.7%) of participants had back problems plus anxiety and a mood disorder, and about 15% had headaches and back problems as well as anxiety and a mood disorder.

“That’s a non-negligible amount of the population that have not just one or two things going on but three and four,” said Mr. Bensken.

These new results underscore how complex these patients can be and the need to integrate medical care among different specialties, he noted.

“We don’t believe it’s the neurologist’s job to also manage the hypertension, but being aware of how prevalent hypertension may be and working with the primary care doctor, or at least checking in with the patient and asking if they’re managing their hypertension, is a real priority,” he said.

Researchers also used the ARM system to identify racial disparities, “which have been largely understudied in the epilepsy context,” said Mr. Bensken.

American Indians and Alaskan Natives had a substantially higher prevalence of developmental disabilities, while Black participants had a higher prevalence of hypertension.

One of the study’s themes was that disparities were not uniform, Mr. Bensken noted. “It wasn’t that in every condition the prevalence was lowest for White individuals and highest for everybody else,” he said.

These results point to the need for a larger study to examine the cultural context of these subgroups and such things as structural racism that might drive disparities, he added.

When researchers examined combinations of comorbidities in individuals in the top quartile of hospitalizations and emergency department visits, they found high users had a much higher disease burden, with 75.8% having anxiety or a mood disorder.

The study highlights that patients with epilepsy on Medicaid are “a high priority population,” said Mr. Bensken.
 

‘Drift down hypothesis’

Commenting on the findings, Fred A. Lado, MD, PhD, director of epilepsy at Northwell Health Eastern and Central Regions, said the increased incidence of comorbidities in patients of low socioeconomic status was not surprising.

“The interesting data here is that we see an even higher incidence among people with epilepsy,” said Dr. Lado, who was not involved with the research.

The study shows how epilepsy exacerbates the effects of low socioeconomic status, he added.

“One of the determinants of socioeconomic status in this case may well be the fact they have seizures and have a limited ability to work and are often more dependent on state assistance and disability support,” Dr. Lado said.

He also referred to the “drift down hypothesis” of chronic disease. “If you have epilepsy and are born into a middle-class family, chances are you will be on disability and can’t work, so you probably have a lower socioeconomic status than your family did as you grew up.”

Dr. Lado noted how “extremely common” mood disorders are in this population and that certain pain syndromes “tracked with those mood disorders.”

“We know mood disorders are more prevalent in people with epilepsy, and now we see that pain-related problems – headache and back pain – are more prevalent in people with epilepsy,” he said.

The data showing “downstream effects of the mood disorders,” from epilepsy to mood disorders to pain disorders, was “very interesting,” Dr. Lado said.

The study was funded by the Centers for Disease Control and Prevention and the National Institute on Minority Health and Health Disparities of the National Institutes of Health. Mr. Bensken has reported receiving research support for this work from the NIH.

A version of this article first appeared on Medscape.com.

A real-world analysis of bulevirtide found a safety and efficacy profile similar to what was seen in earlier clinical trials in the treatment of hepatitis delta virus (HDV) infection.

HDV can only infect patients already carrying hepatitis B virus (HBV), but it causes the most severe form of viral hepatitis as it can progress to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years.

Bulevirtide is a first-in-class medication that mimics the hepatitis B surface antigen, binding to its receptor on hepatocytes and preventing HDV viral particles from binding to it. The drug received conditional marketing approval by the European Medicines Agency in 2020 and has received a breakthrough therapy designation from the U.S. Food and Drug Administration.

The study was presented at the annual meeting of the American Association for the Study of Liver Diseases by Victor De Ledinghen, PhD, who is a professor of hepatology and head of the hepatology and liver transplantation unit at Bordeaux (France) University Hospital.

The early-access program launched after the French National Agency for Medicines and Health Products approved bulevirtide in 2019. It was made available to patients with compensated cirrhosis or severe liver fibrosis (F3) or patients with F2 fibrosis and alanine amino transferase levels more than twice the upper limit of normal for 6 months or more. Patients received bulevirtide alone (n = 77) or in combination with peg-interferon (n = 68), as determined by their physician.

The researchers defined virologic efficacy as HDV RNA levels being undetectable, or decreased by at least 2 log₁₀ from baseline. They defined biochemical efficacy as ALT levels below 40 IU/L.

A per-protocol analysis included all patients in the bulevirtide group, but excluded 12 from the combination group who discontinued peg-interferon (n = 56). Nineteen patients in bulevirtide group had a treatment modification, and seven discontinued treatment. Five in the combination group had a treatment modification, and 14 stopped treatment. At 12 months, there was a greater decline in median log10 IU/mL in the combination group (–5.65 versus –3.64), though the study was not powered to compare the two. At 12 months, the combination group had 93.9% virologic efficacy, compared with 68.3% in the bulevirtide group.

The two groups had similar mean ALT levels at 12 months (48.91 and 48.03 IU/mL, respectively), with more patients in the bulevirtide group having normal ALT levels (<40 IU/L; 48.8% versus 36.4%). At 12 months, 39.0% of the bulevirtide group and 30.3% of the combination group had a combined response, defined as either undetectable HDV RNA or ≥2 log10 from baseline plus normal ALT levels.

Twenty-nine patients in the bulevirtide group had an adverse event, compared with 43 in the combination group. The two groups were similar in the frequency of grade 3-4 adverse events (7 versus 6), discontinuation due to adverse events (2 versus 3), deaths (0 in both), injection-site reactions (2 in both), liver-related adverse events (4 versus 2), and elevated bile acid (76 versus 68).

During the Q&A period following the presentation, Dr. De Ledinghen was asked if he has a preferred regimen for HDV patients. “I think it depends on the tolerance of peg-interferon because of all the side effects with this drug. I think we need to have predictive factors of virological response with or without interferon. At this time, I don’t have a preference, but I think at this time we need to work on predictive factors associated with virologic response,” he said.

The EMA’s conditional bulevirtide approval hinged on results from phase 2 clinical trials, while the phase 3 clinical studies are ongoing. “This was a very unusual step for the EMA to provide what is similar to emergency use approval while the phase 3 clinical trials are still ongoing,” said Anna Lok, MD, who was asked to comment on the study. Dr. Lok is a professor of internal medicine, director of clinical hepatology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.

She noted that the phase 2 studies indicated that the combination with peg-interferon seems to have an additive effect on HDV suppression, while monotherapy with bulevirtide has a greater effect on normalizing ALT levels. The real-world experience confirms these findings.

But the real-world data revealed some concerns. “What really worried me is the large number of patients who required dose modifications or discontinuations, and that seems to be the case in both treatment groups. They didn’t really go into a lot of details [about] why patients needed treatment modifications, but one has to assume that this is due to side effects,” said Dr. Lok.

She also noted that the per-protocol analysis, instead of an intention-to-treat analysis, is a weakness of the study. Additionally, over time, the number of patients analyzed decreased – as many as 40% of patients didn’t have test results at month 12. “It makes you wonder what happened to those patients. Many probably didn’t respond, in which case your overall response rate will be far lower,” said Dr. Lok.

The study was funded by Gilead. Dr. De Ledinghen has financial relationships with Gilead, AbbVie, Echosens, Hologic, Intercept Pharma, Tillotts, Orphalan, Alfasigma, Bristol Myers Squibb, and Siemens Healthineers. Dr. Lok has no relevant financial disclosures.

A real-world analysis of bulevirtide found a safety and efficacy profile similar to what was seen in earlier clinical trials in the treatment of hepatitis delta virus (HDV) infection.

HDV can only infect patients already carrying hepatitis B virus (HBV), but it causes the most severe form of viral hepatitis as it can progress to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years.

Bulevirtide is a first-in-class medication that mimics the hepatitis B surface antigen, binding to its receptor on hepatocytes and preventing HDV viral particles from binding to it. The drug received conditional marketing approval by the European Medicines Agency in 2020 and has received a breakthrough therapy designation from the U.S. Food and Drug Administration.

The study was presented at the annual meeting of the American Association for the Study of Liver Diseases by Victor De Ledinghen, PhD, who is a professor of hepatology and head of the hepatology and liver transplantation unit at Bordeaux (France) University Hospital.

The early-access program launched after the French National Agency for Medicines and Health Products approved bulevirtide in 2019. It was made available to patients with compensated cirrhosis or severe liver fibrosis (F3) or patients with F2 fibrosis and alanine amino transferase levels more than twice the upper limit of normal for 6 months or more. Patients received bulevirtide alone (n = 77) or in combination with peg-interferon (n = 68), as determined by their physician.

The researchers defined virologic efficacy as HDV RNA levels being undetectable, or decreased by at least 2 log₁₀ from baseline. They defined biochemical efficacy as ALT levels below 40 IU/L.

A per-protocol analysis included all patients in the bulevirtide group, but excluded 12 from the combination group who discontinued peg-interferon (n = 56). Nineteen patients in bulevirtide group had a treatment modification, and seven discontinued treatment. Five in the combination group had a treatment modification, and 14 stopped treatment. At 12 months, there was a greater decline in median log10 IU/mL in the combination group (–5.65 versus –3.64), though the study was not powered to compare the two. At 12 months, the combination group had 93.9% virologic efficacy, compared with 68.3% in the bulevirtide group.

The two groups had similar mean ALT levels at 12 months (48.91 and 48.03 IU/mL, respectively), with more patients in the bulevirtide group having normal ALT levels (<40 IU/L; 48.8% versus 36.4%). At 12 months, 39.0% of the bulevirtide group and 30.3% of the combination group had a combined response, defined as either undetectable HDV RNA or ≥2 log10 from baseline plus normal ALT levels.

Twenty-nine patients in the bulevirtide group had an adverse event, compared with 43 in the combination group. The two groups were similar in the frequency of grade 3-4 adverse events (7 versus 6), discontinuation due to adverse events (2 versus 3), deaths (0 in both), injection-site reactions (2 in both), liver-related adverse events (4 versus 2), and elevated bile acid (76 versus 68).

During the Q&A period following the presentation, Dr. De Ledinghen was asked if he has a preferred regimen for HDV patients. “I think it depends on the tolerance of peg-interferon because of all the side effects with this drug. I think we need to have predictive factors of virological response with or without interferon. At this time, I don’t have a preference, but I think at this time we need to work on predictive factors associated with virologic response,” he said.

The EMA’s conditional bulevirtide approval hinged on results from phase 2 clinical trials, while the phase 3 clinical studies are ongoing. “This was a very unusual step for the EMA to provide what is similar to emergency use approval while the phase 3 clinical trials are still ongoing,” said Anna Lok, MD, who was asked to comment on the study. Dr. Lok is a professor of internal medicine, director of clinical hepatology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.

She noted that the phase 2 studies indicated that the combination with peg-interferon seems to have an additive effect on HDV suppression, while monotherapy with bulevirtide has a greater effect on normalizing ALT levels. The real-world experience confirms these findings.

But the real-world data revealed some concerns. “What really worried me is the large number of patients who required dose modifications or discontinuations, and that seems to be the case in both treatment groups. They didn’t really go into a lot of details [about] why patients needed treatment modifications, but one has to assume that this is due to side effects,” said Dr. Lok.

She also noted that the per-protocol analysis, instead of an intention-to-treat analysis, is a weakness of the study. Additionally, over time, the number of patients analyzed decreased – as many as 40% of patients didn’t have test results at month 12. “It makes you wonder what happened to those patients. Many probably didn’t respond, in which case your overall response rate will be far lower,” said Dr. Lok.

The study was funded by Gilead. Dr. De Ledinghen has financial relationships with Gilead, AbbVie, Echosens, Hologic, Intercept Pharma, Tillotts, Orphalan, Alfasigma, Bristol Myers Squibb, and Siemens Healthineers. Dr. Lok has no relevant financial disclosures.

A real-world analysis of bulevirtide found a safety and efficacy profile similar to what was seen in earlier clinical trials in the treatment of hepatitis delta virus (HDV) infection.

HDV can only infect patients already carrying hepatitis B virus (HBV), but it causes the most severe form of viral hepatitis as it can progress to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years.

Bulevirtide is a first-in-class medication that mimics the hepatitis B surface antigen, binding to its receptor on hepatocytes and preventing HDV viral particles from binding to it. The drug received conditional marketing approval by the European Medicines Agency in 2020 and has received a breakthrough therapy designation from the U.S. Food and Drug Administration.

The study was presented at the annual meeting of the American Association for the Study of Liver Diseases by Victor De Ledinghen, PhD, who is a professor of hepatology and head of the hepatology and liver transplantation unit at Bordeaux (France) University Hospital.

The early-access program launched after the French National Agency for Medicines and Health Products approved bulevirtide in 2019. It was made available to patients with compensated cirrhosis or severe liver fibrosis (F3) or patients with F2 fibrosis and alanine amino transferase levels more than twice the upper limit of normal for 6 months or more. Patients received bulevirtide alone (n = 77) or in combination with peg-interferon (n = 68), as determined by their physician.

The researchers defined virologic efficacy as HDV RNA levels being undetectable, or decreased by at least 2 log₁₀ from baseline. They defined biochemical efficacy as ALT levels below 40 IU/L.

A per-protocol analysis included all patients in the bulevirtide group, but excluded 12 from the combination group who discontinued peg-interferon (n = 56). Nineteen patients in bulevirtide group had a treatment modification, and seven discontinued treatment. Five in the combination group had a treatment modification, and 14 stopped treatment. At 12 months, there was a greater decline in median log10 IU/mL in the combination group (–5.65 versus –3.64), though the study was not powered to compare the two. At 12 months, the combination group had 93.9% virologic efficacy, compared with 68.3% in the bulevirtide group.

The two groups had similar mean ALT levels at 12 months (48.91 and 48.03 IU/mL, respectively), with more patients in the bulevirtide group having normal ALT levels (<40 IU/L; 48.8% versus 36.4%). At 12 months, 39.0% of the bulevirtide group and 30.3% of the combination group had a combined response, defined as either undetectable HDV RNA or ≥2 log10 from baseline plus normal ALT levels.

Twenty-nine patients in the bulevirtide group had an adverse event, compared with 43 in the combination group. The two groups were similar in the frequency of grade 3-4 adverse events (7 versus 6), discontinuation due to adverse events (2 versus 3), deaths (0 in both), injection-site reactions (2 in both), liver-related adverse events (4 versus 2), and elevated bile acid (76 versus 68).

During the Q&A period following the presentation, Dr. De Ledinghen was asked if he has a preferred regimen for HDV patients. “I think it depends on the tolerance of peg-interferon because of all the side effects with this drug. I think we need to have predictive factors of virological response with or without interferon. At this time, I don’t have a preference, but I think at this time we need to work on predictive factors associated with virologic response,” he said.

The EMA’s conditional bulevirtide approval hinged on results from phase 2 clinical trials, while the phase 3 clinical studies are ongoing. “This was a very unusual step for the EMA to provide what is similar to emergency use approval while the phase 3 clinical trials are still ongoing,” said Anna Lok, MD, who was asked to comment on the study. Dr. Lok is a professor of internal medicine, director of clinical hepatology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.

She noted that the phase 2 studies indicated that the combination with peg-interferon seems to have an additive effect on HDV suppression, while monotherapy with bulevirtide has a greater effect on normalizing ALT levels. The real-world experience confirms these findings.

But the real-world data revealed some concerns. “What really worried me is the large number of patients who required dose modifications or discontinuations, and that seems to be the case in both treatment groups. They didn’t really go into a lot of details [about] why patients needed treatment modifications, but one has to assume that this is due to side effects,” said Dr. Lok.

She also noted that the per-protocol analysis, instead of an intention-to-treat analysis, is a weakness of the study. Additionally, over time, the number of patients analyzed decreased – as many as 40% of patients didn’t have test results at month 12. “It makes you wonder what happened to those patients. Many probably didn’t respond, in which case your overall response rate will be far lower,” said Dr. Lok.

The study was funded by Gilead. Dr. De Ledinghen has financial relationships with Gilead, AbbVie, Echosens, Hologic, Intercept Pharma, Tillotts, Orphalan, Alfasigma, Bristol Myers Squibb, and Siemens Healthineers. Dr. Lok has no relevant financial disclosures.