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Balanced crystalloid fluids surpass saline for kidney transplant
ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.
“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.
“Balanced crystalloids are cheap, readily available worldwide, and this simple change in kidney transplant practice can easily be implemented in global practice ... almost immediately,” said Dr. Collins, a nephrologist at Royal Adelaide Hospital, Australia.
A 1-L bag of balanced crystalloid fluid is more expensive; however, it has a U.S. retail cost of about $2-$5 per bag, compared with about $1 per bag of saline fluid, Dr. Collins added.
Various other commentators had mixed views. Some agreed with Dr. Collins and said the switch could be made immediately, although one researcher wanted to see more trials. Another wondered why balanced crystalloid fluid hadn’t seemed to provide benefit in studies in acute kidney injury.
Treating 10 patients prevents one delayed graft function
The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.
This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.
Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.
A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.
Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
Chloride is the culprit
“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.
“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.
However, Pascale H. Lane, MD, a pediatric nephrologist with Oklahoma University Health, Oklahoma City, predicted that based on these results, “I think it will be rapidly embraced” by U.S. clinicians. Dr. Lane expressed concern about the availability of an adequate supply of balanced crystalloid fluid, but Dr. Collins said he did not believe supply would be an issue based on current availability.
This was “a beautiful study, very well done, with nice results, and a very easy switch to balanced crystalloid fluids without harm,” commented Richard Lafayette, MD, a nephrologist and professor of medicine at Stanford (Calif.) University.
Success attributed to early treatment
But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.
Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.
The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.
Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.
During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.
The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.
BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.
A version of this article first appeared on Medscape.com.
ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.
“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.
“Balanced crystalloids are cheap, readily available worldwide, and this simple change in kidney transplant practice can easily be implemented in global practice ... almost immediately,” said Dr. Collins, a nephrologist at Royal Adelaide Hospital, Australia.
A 1-L bag of balanced crystalloid fluid is more expensive; however, it has a U.S. retail cost of about $2-$5 per bag, compared with about $1 per bag of saline fluid, Dr. Collins added.
Various other commentators had mixed views. Some agreed with Dr. Collins and said the switch could be made immediately, although one researcher wanted to see more trials. Another wondered why balanced crystalloid fluid hadn’t seemed to provide benefit in studies in acute kidney injury.
Treating 10 patients prevents one delayed graft function
The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.
This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.
Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.
A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.
Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
Chloride is the culprit
“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.
“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.
However, Pascale H. Lane, MD, a pediatric nephrologist with Oklahoma University Health, Oklahoma City, predicted that based on these results, “I think it will be rapidly embraced” by U.S. clinicians. Dr. Lane expressed concern about the availability of an adequate supply of balanced crystalloid fluid, but Dr. Collins said he did not believe supply would be an issue based on current availability.
This was “a beautiful study, very well done, with nice results, and a very easy switch to balanced crystalloid fluids without harm,” commented Richard Lafayette, MD, a nephrologist and professor of medicine at Stanford (Calif.) University.
Success attributed to early treatment
But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.
Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.
The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.
Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.
During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.
The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.
BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.
A version of this article first appeared on Medscape.com.
ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.
“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.
“Balanced crystalloids are cheap, readily available worldwide, and this simple change in kidney transplant practice can easily be implemented in global practice ... almost immediately,” said Dr. Collins, a nephrologist at Royal Adelaide Hospital, Australia.
A 1-L bag of balanced crystalloid fluid is more expensive; however, it has a U.S. retail cost of about $2-$5 per bag, compared with about $1 per bag of saline fluid, Dr. Collins added.
Various other commentators had mixed views. Some agreed with Dr. Collins and said the switch could be made immediately, although one researcher wanted to see more trials. Another wondered why balanced crystalloid fluid hadn’t seemed to provide benefit in studies in acute kidney injury.
Treating 10 patients prevents one delayed graft function
The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.
This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.
Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.
A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.
Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
Chloride is the culprit
“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.
“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.
However, Pascale H. Lane, MD, a pediatric nephrologist with Oklahoma University Health, Oklahoma City, predicted that based on these results, “I think it will be rapidly embraced” by U.S. clinicians. Dr. Lane expressed concern about the availability of an adequate supply of balanced crystalloid fluid, but Dr. Collins said he did not believe supply would be an issue based on current availability.
This was “a beautiful study, very well done, with nice results, and a very easy switch to balanced crystalloid fluids without harm,” commented Richard Lafayette, MD, a nephrologist and professor of medicine at Stanford (Calif.) University.
Success attributed to early treatment
But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.
Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.
The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.
Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.
During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.
The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.
BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.
A version of this article first appeared on Medscape.com.
AT KIDNEY WEEK 2022
EHR reminders boost well-child visits, vax rates
Reminder messages sent through electronic health records (EHRs) to patient portals increased rates of scheduling and completion of well-child visits for those overdue for well care, as well as vaccination rates, according to data published today in JAMA Network Open.
Anne E. Berset, BA, with general and community pediatrics at Cincinnati Children’s Hospital, led a randomized clinical trial conducted at three academic primary care practices from July 30 to Oct. 4, 2021.
The practices serve a mostly non-Hispanic Black, low-income population and provide more than 60,000 visits a year to 30,000 patients.
The study population included 945 patients, 62.4% of them non-Hispanic Black and 807 (85.4%) covered by public insurance.
Standard message and tailored message compared
The study population was randomized to get either a standard reminder message, a tailored message, or no message (control group).
The standard messages referenced the patient’s first name and reminded parents their child was due for a well-child visit, and asked them to schedule it using the portal or by calling the number provided.
The tailored message added the date of the last well-child check-up “to address distortions of time perception experienced during the pandemic,” the authors write.
The primary outcome was whether the well-child visit was completed within 8 weeks. Other outcomes included whether a well-child visit was scheduled within 2 weeks of the first reminder message and whether the patient received a COVID-19 vaccine within 8 weeks of the reminder.
Reminders outperform control group
There was a significant increase in scheduling and completion of appointments after parents received the standard and tailored messages compared with controls.
The results with the COVID reminders were particularly striking. While only 3.7% of the eligible patients got a vaccine when they got no message, 17.3% got the vaccine in that time frame when they got the standard message. Interestingly, only 2.7% received the shot after the tailored message.
J. Howard Smart, MD, with Sharp HealthCare in San Diego, told this publication he was not surprised that a patient portal reminder would increase the rate of scheduling overdue well-child visits. “Parents may indeed have lost track of when their children need to have check-ups” during the pandemic, he said.
Reminders without tailored information more effective
He said he was surprised, just as the investigators were, that the reminders without the tailored information seemed to be more effective for some outcomes.
The authors explained that a focus group found “that families with patient portal accounts prefer straightforward, brief, and user-friendly messages.”
That may help explain why the standard message outperformed the tailored message, the authors write.
“Families may have been distracted by the additional information related to the child’s age and date of last WCC [well-child check-up] in the tailored message,” they write.
Dr. Smart said, “Their discussion of why this might be the case sounds reasonable. Simple, short messages may be better received.”
“Evidence like this should stimulate portal software vendors to make this kind of outgoing messaging easy to set up for providers,” he said.
Simple measure, large effect
Tim Joos, MD, a pediatrician in Seattle, told this publication he “was impressed by how such a simple measure increased rates of well-child care completion.”
Minority and low-income patients have traditionally had more access challenges to completing health care visits and vaccinations on schedule, he noted, so he was glad to see positive results from the intervention in this study population.
The authors note that research on portal messages have largely looked at use in non-Hispanic Whites and the privately insured.
Dr. Joos said the intervention also offers convenience in that once patients get into the portal, they can schedule an appointment there without having to wait on the phone or leave a message.
Funding/support was received from the Center for Clinical and Translational Science and Training at the University of Cincinnati, which is funded by the National Institutes of Health. William B. Brinkman, MD, MEd, MSc, one of the study authors, holds common stock in Pfizer, Merck, Abbott Laboratories, Viatris, and Johnson & Johnson outside the submitted work. No other author disclosures were reported. Dr. Smart and Dr. Joos declared no relevant financial relationships.
Reminder messages sent through electronic health records (EHRs) to patient portals increased rates of scheduling and completion of well-child visits for those overdue for well care, as well as vaccination rates, according to data published today in JAMA Network Open.
Anne E. Berset, BA, with general and community pediatrics at Cincinnati Children’s Hospital, led a randomized clinical trial conducted at three academic primary care practices from July 30 to Oct. 4, 2021.
The practices serve a mostly non-Hispanic Black, low-income population and provide more than 60,000 visits a year to 30,000 patients.
The study population included 945 patients, 62.4% of them non-Hispanic Black and 807 (85.4%) covered by public insurance.
Standard message and tailored message compared
The study population was randomized to get either a standard reminder message, a tailored message, or no message (control group).
The standard messages referenced the patient’s first name and reminded parents their child was due for a well-child visit, and asked them to schedule it using the portal or by calling the number provided.
The tailored message added the date of the last well-child check-up “to address distortions of time perception experienced during the pandemic,” the authors write.
The primary outcome was whether the well-child visit was completed within 8 weeks. Other outcomes included whether a well-child visit was scheduled within 2 weeks of the first reminder message and whether the patient received a COVID-19 vaccine within 8 weeks of the reminder.
Reminders outperform control group
There was a significant increase in scheduling and completion of appointments after parents received the standard and tailored messages compared with controls.
The results with the COVID reminders were particularly striking. While only 3.7% of the eligible patients got a vaccine when they got no message, 17.3% got the vaccine in that time frame when they got the standard message. Interestingly, only 2.7% received the shot after the tailored message.
J. Howard Smart, MD, with Sharp HealthCare in San Diego, told this publication he was not surprised that a patient portal reminder would increase the rate of scheduling overdue well-child visits. “Parents may indeed have lost track of when their children need to have check-ups” during the pandemic, he said.
Reminders without tailored information more effective
He said he was surprised, just as the investigators were, that the reminders without the tailored information seemed to be more effective for some outcomes.
The authors explained that a focus group found “that families with patient portal accounts prefer straightforward, brief, and user-friendly messages.”
That may help explain why the standard message outperformed the tailored message, the authors write.
“Families may have been distracted by the additional information related to the child’s age and date of last WCC [well-child check-up] in the tailored message,” they write.
Dr. Smart said, “Their discussion of why this might be the case sounds reasonable. Simple, short messages may be better received.”
“Evidence like this should stimulate portal software vendors to make this kind of outgoing messaging easy to set up for providers,” he said.
Simple measure, large effect
Tim Joos, MD, a pediatrician in Seattle, told this publication he “was impressed by how such a simple measure increased rates of well-child care completion.”
Minority and low-income patients have traditionally had more access challenges to completing health care visits and vaccinations on schedule, he noted, so he was glad to see positive results from the intervention in this study population.
The authors note that research on portal messages have largely looked at use in non-Hispanic Whites and the privately insured.
Dr. Joos said the intervention also offers convenience in that once patients get into the portal, they can schedule an appointment there without having to wait on the phone or leave a message.
Funding/support was received from the Center for Clinical and Translational Science and Training at the University of Cincinnati, which is funded by the National Institutes of Health. William B. Brinkman, MD, MEd, MSc, one of the study authors, holds common stock in Pfizer, Merck, Abbott Laboratories, Viatris, and Johnson & Johnson outside the submitted work. No other author disclosures were reported. Dr. Smart and Dr. Joos declared no relevant financial relationships.
Reminder messages sent through electronic health records (EHRs) to patient portals increased rates of scheduling and completion of well-child visits for those overdue for well care, as well as vaccination rates, according to data published today in JAMA Network Open.
Anne E. Berset, BA, with general and community pediatrics at Cincinnati Children’s Hospital, led a randomized clinical trial conducted at three academic primary care practices from July 30 to Oct. 4, 2021.
The practices serve a mostly non-Hispanic Black, low-income population and provide more than 60,000 visits a year to 30,000 patients.
The study population included 945 patients, 62.4% of them non-Hispanic Black and 807 (85.4%) covered by public insurance.
Standard message and tailored message compared
The study population was randomized to get either a standard reminder message, a tailored message, or no message (control group).
The standard messages referenced the patient’s first name and reminded parents their child was due for a well-child visit, and asked them to schedule it using the portal or by calling the number provided.
The tailored message added the date of the last well-child check-up “to address distortions of time perception experienced during the pandemic,” the authors write.
The primary outcome was whether the well-child visit was completed within 8 weeks. Other outcomes included whether a well-child visit was scheduled within 2 weeks of the first reminder message and whether the patient received a COVID-19 vaccine within 8 weeks of the reminder.
Reminders outperform control group
There was a significant increase in scheduling and completion of appointments after parents received the standard and tailored messages compared with controls.
The results with the COVID reminders were particularly striking. While only 3.7% of the eligible patients got a vaccine when they got no message, 17.3% got the vaccine in that time frame when they got the standard message. Interestingly, only 2.7% received the shot after the tailored message.
J. Howard Smart, MD, with Sharp HealthCare in San Diego, told this publication he was not surprised that a patient portal reminder would increase the rate of scheduling overdue well-child visits. “Parents may indeed have lost track of when their children need to have check-ups” during the pandemic, he said.
Reminders without tailored information more effective
He said he was surprised, just as the investigators were, that the reminders without the tailored information seemed to be more effective for some outcomes.
The authors explained that a focus group found “that families with patient portal accounts prefer straightforward, brief, and user-friendly messages.”
That may help explain why the standard message outperformed the tailored message, the authors write.
“Families may have been distracted by the additional information related to the child’s age and date of last WCC [well-child check-up] in the tailored message,” they write.
Dr. Smart said, “Their discussion of why this might be the case sounds reasonable. Simple, short messages may be better received.”
“Evidence like this should stimulate portal software vendors to make this kind of outgoing messaging easy to set up for providers,” he said.
Simple measure, large effect
Tim Joos, MD, a pediatrician in Seattle, told this publication he “was impressed by how such a simple measure increased rates of well-child care completion.”
Minority and low-income patients have traditionally had more access challenges to completing health care visits and vaccinations on schedule, he noted, so he was glad to see positive results from the intervention in this study population.
The authors note that research on portal messages have largely looked at use in non-Hispanic Whites and the privately insured.
Dr. Joos said the intervention also offers convenience in that once patients get into the portal, they can schedule an appointment there without having to wait on the phone or leave a message.
Funding/support was received from the Center for Clinical and Translational Science and Training at the University of Cincinnati, which is funded by the National Institutes of Health. William B. Brinkman, MD, MEd, MSc, one of the study authors, holds common stock in Pfizer, Merck, Abbott Laboratories, Viatris, and Johnson & Johnson outside the submitted work. No other author disclosures were reported. Dr. Smart and Dr. Joos declared no relevant financial relationships.
FROM JAMA NETWORK OPEN
Medical school culinary medicine programs grow despite limited funding
The way he sees it, the stakes couldn’t be higher. He believes doctors need to see food as medicine to be able to stem the tide of chronic disease.
About 6 in 10 adults in the United States live with chronic diseases, according to the Centers for Disease Control and Prevention, costing $4.1 trillion in annual health care costs. Adult obesity rates are rising, as are obesity-related conditions such as heart disease, stroke, type 2 diabetes, and certain types of cancer.
To turn the tide, Dr. Marvasti created a culinary medicine program in 2020 in collaboration with the University of Arizona Cooperative Extension and local chefs.
Dr. Marvasti, who is board certified in family medicine, graduated from the University of Arizona, Phoenix, where he serves as the director of the medical school’s Culinary Medicine Program.
The program offers an elective course for third- and fourth-year medical students, which introduces the evidence-based field of culinary medicine. Dr Marvasti’s goal is for the course to teach students how to use this science and the joy of cooking to improve long-term health outcomes for their patients.
As part of Dr. Marvasti’s program, students learn cooking fundamentals through chef demonstrations and hands-on practice – to teach students how food can be used to prevent and treat many chronic diseases.
One of the dishes students learn to make includes a quinoa salad made with cucumber, onion, bell peppers, corn, cherry tomatoes, beans, garlic, olive oil, and lemon juice. Another recipe includes a healthier take on dessert: Dark chocolate mousse made with three large, ripe avocados, dark chocolate powder, three tablespoons of agave or maple, coconut cream, nondairy milk, salt, and vanilla. Dr. Marvasti and his team are set to build out the existing program to develop additional resources for medically underserved and rural communities in Arizona, according to a statement from the university. These plans will be funded by a $750,000 grant from Novo Nordisk.
“We’re going to develop an open education curriculum to share, so it’s open access to everyone,” said Dr. Marvasti, who is also director of Public Health, Prevention and Health Promotion and an associate professor at the university. “It can be adaptable at the undergraduate, graduate, and postgraduate level.”
Dr. Marvasti and his colleagues at the University of Arizona aren’t alone. In fact, culinary medicine programs are sprouting some serious legs.
Culinary medicine programs catch on
Jaclyn Albin, MD, CCMS, an associate professor in the departments of internal medicine and pediatrics at UT Southwestern Medical Center, Dallas, conducted a scoping review of the literature on culinary medicine programs for medical students.* Her purpose was to learn how the programs were structured and how they assessed student knowledge and attitudes regarding nutrition counseling for patients.
Dr. Albin and her colleagues performed an initial literature search between June 1 and Aug. 1, 2020, of papers published between Jan. 1, 2012, and Aug. 1, 2020 – excluding some newer programs such as the one at the University of Arizona. The results of their research were published in Academic Medicine.
Ultimately, the authors identified and examined 34 programs offering medical student–focused culinary medicine courses.
Program instructors typically included a team of physicians, dietitians, chefs, and other professionals, the study found.
Most program participants exclusively taught medical students, though the training years of participants varied among programs, and they included first-, second-, third-, and fourth-year students. Some programs allowed students from outside their respective medical school to participate in the trainings.
As for the formats of the program, most included cohorts of 10-20 students attending multiple 2- to 3-hour sessions over the course of several months. The University of Alabama at Birmingham offers one of the longest courses, which spans 4-5 months, according to the paper. In contrast, the University of Rochester (N.Y.) program offers only a 1-day lab divided into four sessions, with each session lasting about 2 hours.
The culinary medicine programs’ course sessions tended to include a 10- to 30-minute didactic session involving videos, research articles, culinary theories, and other lectures, a 60- to 90-minute hands-on cooking session, and a 30-minute discussion around nutrition, culture, and patient care.
Most programs used pre- and post-program surveys to evaluate outcomes, though results varied between programs, according to the study. While each program evaluation had different metrics, the surveys generally revealed students felt more confident discussing dietary interventions with patients and in their own cooking skills following completion.
Course correction
Most of those programs are unfunded or minimally funded, Dr. Albin said.
Her own program, which is immensely popular with medical students, is one she teaches on a volunteer basis.
“I do this for free, in the evenings, because I believe in it,” she said.
Medical school education real estate is limited, so convincing medical schools to add something to the curriculum is difficult, Dr. Albin noted.
But it’s worth it, she said, because nutrition is the underpinning of so many diseases.
“Food is the top risk factor for early death in the U.S.,” Dr. Albin said. “I like to say that five times in a row. People have not digested it.”
During her culinary medicine courses, she also asks her medical students: “Who is comfortable in the kitchen?” Some sheepishly raise their hands, she said. Some don’t. Many don’t know anything about cooking.
Then she teaches students about healthy food and how to make it. As part of her program, medical students are given a pantry starter kit with olive oil and a variety of spices to take home and use.
Some recipes Dr. Albin teaches includes mango chili shrimp salad with lime vinaigrette, eggplant sliders, yellow vegetable curry, and strawberry banana chia pudding.
“If you figure out how to do it for your own busy, everyday life, you are now empowered to tell someone else about it,” she said.
A dietitian’s involvement
Milette Siler, RD, LD, CCMS, works with Dr. Albin to educate medical students and patients about food as medicine. A significant chunk of her job involves teaching future doctors what dietitians do.
When the class starts, many students don’t know two of the five basic things dietitians do, Ms. Siler said. By the end of the class, all students know what a dietitian does.
That’s important as students go on to become doctors.
“For us to remove barriers to care, we have to acknowledge most patients’ entry into health care is their physician,” she said. “The dietitian is often a referral. Doctors need to know enough to do no harm.”
Clinicians are often siloed, she said, and the key to better serving patients is partnership, transparency, and relationships. “I think everybody is at a point where everyone is saying what we’re doing isn’t working,” she said. “The American public deserves better, physicians deserve better, and clinicians deserve better.”
Popular with students
While the old guard has been slow to embrace the shift, her students have helped drive the growth of the culinary medicine field, Dr. Albin said.
“They are not settling for the inadequacy that somehow the rest of us did,” she continued. “I’m so hopeful for the future of the health system. We have a generation of people who will not stand for neglecting the most vital elements.”
Lyndon Bui, a second-year medical student at the University of Arizona, Phoenix, is an example of one of these people.
As a member of a culinary medicine interest group on campus, he said, he has learned a lot about the importance of diet for long-term health. This has given him confidence to talk about food and nutrition.
His group does cooking demos at the Phoenix Farmers Market using food from various local vendors. They usually make a salad from local greens and cook seasonal veggies in a stir fry, he said.
They’ve previously made salad with microgreens – young seedlings of edible vegetables and herbs – and pomegranate seeds with a honey mustard vinaigrette, eggplant or cucumber, and hummus on pita bread, as well as almond butter and honey sandwiches, according to the university.
The group also talks with people in the community, answers questions, and learns about community needs.
Mr. Bui’s participation in this group has helped him cultivate a passion for community outreach that he wants to incorporate into his career.
“I feel like I have the knowledge to provide better advice to patients,” he said. “Knowing all these things about food, I feel more comfortable talking about it and more inclined to refer to a dietitian when maybe I wouldn’t have before.”
Family physician applauds culinary medicine programs
When Angie Neison, MD, CCMS, went to medical school, she was surprised there wasn’t more education on nutrition.
In fact, on average, physicians receive less than 20 hours of nutrition education, according to the University of Arizona.
Now 15 years into her career as a family physician, Dr. Neison says nutrition is a huge part of her practice. She spends time working to bust myths about nutrition for her patients – including that healthy food is boring and bland, that making it is time consuming, and that healthy food is expensive. She also spends time teaching aspects of culinary medicine to her colleagues – many of whom are well into their careers – so they can better serve their patients.
It’s worth it to spend time learning about nutrition, she said, whether that’s as a medical student in a culinary medicine program or a practicing physician taking additional courses.
Nutrition education in medical school hasn’t been a priority, she said, maybe because there is so much to learn, or maybe because there is no money to be made in prevention.
“If doctors learn it, they are able to better guide patients,” she said.
Correction, 11/29/22: An earlier version of this article misstated Dr. Albin's institution.
The way he sees it, the stakes couldn’t be higher. He believes doctors need to see food as medicine to be able to stem the tide of chronic disease.
About 6 in 10 adults in the United States live with chronic diseases, according to the Centers for Disease Control and Prevention, costing $4.1 trillion in annual health care costs. Adult obesity rates are rising, as are obesity-related conditions such as heart disease, stroke, type 2 diabetes, and certain types of cancer.
To turn the tide, Dr. Marvasti created a culinary medicine program in 2020 in collaboration with the University of Arizona Cooperative Extension and local chefs.
Dr. Marvasti, who is board certified in family medicine, graduated from the University of Arizona, Phoenix, where he serves as the director of the medical school’s Culinary Medicine Program.
The program offers an elective course for third- and fourth-year medical students, which introduces the evidence-based field of culinary medicine. Dr Marvasti’s goal is for the course to teach students how to use this science and the joy of cooking to improve long-term health outcomes for their patients.
As part of Dr. Marvasti’s program, students learn cooking fundamentals through chef demonstrations and hands-on practice – to teach students how food can be used to prevent and treat many chronic diseases.
One of the dishes students learn to make includes a quinoa salad made with cucumber, onion, bell peppers, corn, cherry tomatoes, beans, garlic, olive oil, and lemon juice. Another recipe includes a healthier take on dessert: Dark chocolate mousse made with three large, ripe avocados, dark chocolate powder, three tablespoons of agave or maple, coconut cream, nondairy milk, salt, and vanilla. Dr. Marvasti and his team are set to build out the existing program to develop additional resources for medically underserved and rural communities in Arizona, according to a statement from the university. These plans will be funded by a $750,000 grant from Novo Nordisk.
“We’re going to develop an open education curriculum to share, so it’s open access to everyone,” said Dr. Marvasti, who is also director of Public Health, Prevention and Health Promotion and an associate professor at the university. “It can be adaptable at the undergraduate, graduate, and postgraduate level.”
Dr. Marvasti and his colleagues at the University of Arizona aren’t alone. In fact, culinary medicine programs are sprouting some serious legs.
Culinary medicine programs catch on
Jaclyn Albin, MD, CCMS, an associate professor in the departments of internal medicine and pediatrics at UT Southwestern Medical Center, Dallas, conducted a scoping review of the literature on culinary medicine programs for medical students.* Her purpose was to learn how the programs were structured and how they assessed student knowledge and attitudes regarding nutrition counseling for patients.
Dr. Albin and her colleagues performed an initial literature search between June 1 and Aug. 1, 2020, of papers published between Jan. 1, 2012, and Aug. 1, 2020 – excluding some newer programs such as the one at the University of Arizona. The results of their research were published in Academic Medicine.
Ultimately, the authors identified and examined 34 programs offering medical student–focused culinary medicine courses.
Program instructors typically included a team of physicians, dietitians, chefs, and other professionals, the study found.
Most program participants exclusively taught medical students, though the training years of participants varied among programs, and they included first-, second-, third-, and fourth-year students. Some programs allowed students from outside their respective medical school to participate in the trainings.
As for the formats of the program, most included cohorts of 10-20 students attending multiple 2- to 3-hour sessions over the course of several months. The University of Alabama at Birmingham offers one of the longest courses, which spans 4-5 months, according to the paper. In contrast, the University of Rochester (N.Y.) program offers only a 1-day lab divided into four sessions, with each session lasting about 2 hours.
The culinary medicine programs’ course sessions tended to include a 10- to 30-minute didactic session involving videos, research articles, culinary theories, and other lectures, a 60- to 90-minute hands-on cooking session, and a 30-minute discussion around nutrition, culture, and patient care.
Most programs used pre- and post-program surveys to evaluate outcomes, though results varied between programs, according to the study. While each program evaluation had different metrics, the surveys generally revealed students felt more confident discussing dietary interventions with patients and in their own cooking skills following completion.
Course correction
Most of those programs are unfunded or minimally funded, Dr. Albin said.
Her own program, which is immensely popular with medical students, is one she teaches on a volunteer basis.
“I do this for free, in the evenings, because I believe in it,” she said.
Medical school education real estate is limited, so convincing medical schools to add something to the curriculum is difficult, Dr. Albin noted.
But it’s worth it, she said, because nutrition is the underpinning of so many diseases.
“Food is the top risk factor for early death in the U.S.,” Dr. Albin said. “I like to say that five times in a row. People have not digested it.”
During her culinary medicine courses, she also asks her medical students: “Who is comfortable in the kitchen?” Some sheepishly raise their hands, she said. Some don’t. Many don’t know anything about cooking.
Then she teaches students about healthy food and how to make it. As part of her program, medical students are given a pantry starter kit with olive oil and a variety of spices to take home and use.
Some recipes Dr. Albin teaches includes mango chili shrimp salad with lime vinaigrette, eggplant sliders, yellow vegetable curry, and strawberry banana chia pudding.
“If you figure out how to do it for your own busy, everyday life, you are now empowered to tell someone else about it,” she said.
A dietitian’s involvement
Milette Siler, RD, LD, CCMS, works with Dr. Albin to educate medical students and patients about food as medicine. A significant chunk of her job involves teaching future doctors what dietitians do.
When the class starts, many students don’t know two of the five basic things dietitians do, Ms. Siler said. By the end of the class, all students know what a dietitian does.
That’s important as students go on to become doctors.
“For us to remove barriers to care, we have to acknowledge most patients’ entry into health care is their physician,” she said. “The dietitian is often a referral. Doctors need to know enough to do no harm.”
Clinicians are often siloed, she said, and the key to better serving patients is partnership, transparency, and relationships. “I think everybody is at a point where everyone is saying what we’re doing isn’t working,” she said. “The American public deserves better, physicians deserve better, and clinicians deserve better.”
Popular with students
While the old guard has been slow to embrace the shift, her students have helped drive the growth of the culinary medicine field, Dr. Albin said.
“They are not settling for the inadequacy that somehow the rest of us did,” she continued. “I’m so hopeful for the future of the health system. We have a generation of people who will not stand for neglecting the most vital elements.”
Lyndon Bui, a second-year medical student at the University of Arizona, Phoenix, is an example of one of these people.
As a member of a culinary medicine interest group on campus, he said, he has learned a lot about the importance of diet for long-term health. This has given him confidence to talk about food and nutrition.
His group does cooking demos at the Phoenix Farmers Market using food from various local vendors. They usually make a salad from local greens and cook seasonal veggies in a stir fry, he said.
They’ve previously made salad with microgreens – young seedlings of edible vegetables and herbs – and pomegranate seeds with a honey mustard vinaigrette, eggplant or cucumber, and hummus on pita bread, as well as almond butter and honey sandwiches, according to the university.
The group also talks with people in the community, answers questions, and learns about community needs.
Mr. Bui’s participation in this group has helped him cultivate a passion for community outreach that he wants to incorporate into his career.
“I feel like I have the knowledge to provide better advice to patients,” he said. “Knowing all these things about food, I feel more comfortable talking about it and more inclined to refer to a dietitian when maybe I wouldn’t have before.”
Family physician applauds culinary medicine programs
When Angie Neison, MD, CCMS, went to medical school, she was surprised there wasn’t more education on nutrition.
In fact, on average, physicians receive less than 20 hours of nutrition education, according to the University of Arizona.
Now 15 years into her career as a family physician, Dr. Neison says nutrition is a huge part of her practice. She spends time working to bust myths about nutrition for her patients – including that healthy food is boring and bland, that making it is time consuming, and that healthy food is expensive. She also spends time teaching aspects of culinary medicine to her colleagues – many of whom are well into their careers – so they can better serve their patients.
It’s worth it to spend time learning about nutrition, she said, whether that’s as a medical student in a culinary medicine program or a practicing physician taking additional courses.
Nutrition education in medical school hasn’t been a priority, she said, maybe because there is so much to learn, or maybe because there is no money to be made in prevention.
“If doctors learn it, they are able to better guide patients,” she said.
Correction, 11/29/22: An earlier version of this article misstated Dr. Albin's institution.
The way he sees it, the stakes couldn’t be higher. He believes doctors need to see food as medicine to be able to stem the tide of chronic disease.
About 6 in 10 adults in the United States live with chronic diseases, according to the Centers for Disease Control and Prevention, costing $4.1 trillion in annual health care costs. Adult obesity rates are rising, as are obesity-related conditions such as heart disease, stroke, type 2 diabetes, and certain types of cancer.
To turn the tide, Dr. Marvasti created a culinary medicine program in 2020 in collaboration with the University of Arizona Cooperative Extension and local chefs.
Dr. Marvasti, who is board certified in family medicine, graduated from the University of Arizona, Phoenix, where he serves as the director of the medical school’s Culinary Medicine Program.
The program offers an elective course for third- and fourth-year medical students, which introduces the evidence-based field of culinary medicine. Dr Marvasti’s goal is for the course to teach students how to use this science and the joy of cooking to improve long-term health outcomes for their patients.
As part of Dr. Marvasti’s program, students learn cooking fundamentals through chef demonstrations and hands-on practice – to teach students how food can be used to prevent and treat many chronic diseases.
One of the dishes students learn to make includes a quinoa salad made with cucumber, onion, bell peppers, corn, cherry tomatoes, beans, garlic, olive oil, and lemon juice. Another recipe includes a healthier take on dessert: Dark chocolate mousse made with three large, ripe avocados, dark chocolate powder, three tablespoons of agave or maple, coconut cream, nondairy milk, salt, and vanilla. Dr. Marvasti and his team are set to build out the existing program to develop additional resources for medically underserved and rural communities in Arizona, according to a statement from the university. These plans will be funded by a $750,000 grant from Novo Nordisk.
“We’re going to develop an open education curriculum to share, so it’s open access to everyone,” said Dr. Marvasti, who is also director of Public Health, Prevention and Health Promotion and an associate professor at the university. “It can be adaptable at the undergraduate, graduate, and postgraduate level.”
Dr. Marvasti and his colleagues at the University of Arizona aren’t alone. In fact, culinary medicine programs are sprouting some serious legs.
Culinary medicine programs catch on
Jaclyn Albin, MD, CCMS, an associate professor in the departments of internal medicine and pediatrics at UT Southwestern Medical Center, Dallas, conducted a scoping review of the literature on culinary medicine programs for medical students.* Her purpose was to learn how the programs were structured and how they assessed student knowledge and attitudes regarding nutrition counseling for patients.
Dr. Albin and her colleagues performed an initial literature search between June 1 and Aug. 1, 2020, of papers published between Jan. 1, 2012, and Aug. 1, 2020 – excluding some newer programs such as the one at the University of Arizona. The results of their research were published in Academic Medicine.
Ultimately, the authors identified and examined 34 programs offering medical student–focused culinary medicine courses.
Program instructors typically included a team of physicians, dietitians, chefs, and other professionals, the study found.
Most program participants exclusively taught medical students, though the training years of participants varied among programs, and they included first-, second-, third-, and fourth-year students. Some programs allowed students from outside their respective medical school to participate in the trainings.
As for the formats of the program, most included cohorts of 10-20 students attending multiple 2- to 3-hour sessions over the course of several months. The University of Alabama at Birmingham offers one of the longest courses, which spans 4-5 months, according to the paper. In contrast, the University of Rochester (N.Y.) program offers only a 1-day lab divided into four sessions, with each session lasting about 2 hours.
The culinary medicine programs’ course sessions tended to include a 10- to 30-minute didactic session involving videos, research articles, culinary theories, and other lectures, a 60- to 90-minute hands-on cooking session, and a 30-minute discussion around nutrition, culture, and patient care.
Most programs used pre- and post-program surveys to evaluate outcomes, though results varied between programs, according to the study. While each program evaluation had different metrics, the surveys generally revealed students felt more confident discussing dietary interventions with patients and in their own cooking skills following completion.
Course correction
Most of those programs are unfunded or minimally funded, Dr. Albin said.
Her own program, which is immensely popular with medical students, is one she teaches on a volunteer basis.
“I do this for free, in the evenings, because I believe in it,” she said.
Medical school education real estate is limited, so convincing medical schools to add something to the curriculum is difficult, Dr. Albin noted.
But it’s worth it, she said, because nutrition is the underpinning of so many diseases.
“Food is the top risk factor for early death in the U.S.,” Dr. Albin said. “I like to say that five times in a row. People have not digested it.”
During her culinary medicine courses, she also asks her medical students: “Who is comfortable in the kitchen?” Some sheepishly raise their hands, she said. Some don’t. Many don’t know anything about cooking.
Then she teaches students about healthy food and how to make it. As part of her program, medical students are given a pantry starter kit with olive oil and a variety of spices to take home and use.
Some recipes Dr. Albin teaches includes mango chili shrimp salad with lime vinaigrette, eggplant sliders, yellow vegetable curry, and strawberry banana chia pudding.
“If you figure out how to do it for your own busy, everyday life, you are now empowered to tell someone else about it,” she said.
A dietitian’s involvement
Milette Siler, RD, LD, CCMS, works with Dr. Albin to educate medical students and patients about food as medicine. A significant chunk of her job involves teaching future doctors what dietitians do.
When the class starts, many students don’t know two of the five basic things dietitians do, Ms. Siler said. By the end of the class, all students know what a dietitian does.
That’s important as students go on to become doctors.
“For us to remove barriers to care, we have to acknowledge most patients’ entry into health care is their physician,” she said. “The dietitian is often a referral. Doctors need to know enough to do no harm.”
Clinicians are often siloed, she said, and the key to better serving patients is partnership, transparency, and relationships. “I think everybody is at a point where everyone is saying what we’re doing isn’t working,” she said. “The American public deserves better, physicians deserve better, and clinicians deserve better.”
Popular with students
While the old guard has been slow to embrace the shift, her students have helped drive the growth of the culinary medicine field, Dr. Albin said.
“They are not settling for the inadequacy that somehow the rest of us did,” she continued. “I’m so hopeful for the future of the health system. We have a generation of people who will not stand for neglecting the most vital elements.”
Lyndon Bui, a second-year medical student at the University of Arizona, Phoenix, is an example of one of these people.
As a member of a culinary medicine interest group on campus, he said, he has learned a lot about the importance of diet for long-term health. This has given him confidence to talk about food and nutrition.
His group does cooking demos at the Phoenix Farmers Market using food from various local vendors. They usually make a salad from local greens and cook seasonal veggies in a stir fry, he said.
They’ve previously made salad with microgreens – young seedlings of edible vegetables and herbs – and pomegranate seeds with a honey mustard vinaigrette, eggplant or cucumber, and hummus on pita bread, as well as almond butter and honey sandwiches, according to the university.
The group also talks with people in the community, answers questions, and learns about community needs.
Mr. Bui’s participation in this group has helped him cultivate a passion for community outreach that he wants to incorporate into his career.
“I feel like I have the knowledge to provide better advice to patients,” he said. “Knowing all these things about food, I feel more comfortable talking about it and more inclined to refer to a dietitian when maybe I wouldn’t have before.”
Family physician applauds culinary medicine programs
When Angie Neison, MD, CCMS, went to medical school, she was surprised there wasn’t more education on nutrition.
In fact, on average, physicians receive less than 20 hours of nutrition education, according to the University of Arizona.
Now 15 years into her career as a family physician, Dr. Neison says nutrition is a huge part of her practice. She spends time working to bust myths about nutrition for her patients – including that healthy food is boring and bland, that making it is time consuming, and that healthy food is expensive. She also spends time teaching aspects of culinary medicine to her colleagues – many of whom are well into their careers – so they can better serve their patients.
It’s worth it to spend time learning about nutrition, she said, whether that’s as a medical student in a culinary medicine program or a practicing physician taking additional courses.
Nutrition education in medical school hasn’t been a priority, she said, maybe because there is so much to learn, or maybe because there is no money to be made in prevention.
“If doctors learn it, they are able to better guide patients,” she said.
Correction, 11/29/22: An earlier version of this article misstated Dr. Albin's institution.
FROM ACADEMIC MEDICINE
Baxdrostat slashes BP in resistant hypertension: BrigHTN
CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.
The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.
After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).
The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).
Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.
The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
Threading the needle
For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.
What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.
“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.
Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.
Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
‘A bright future’
“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.
She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.
“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”
Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.
Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.
Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.
Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.
At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.
The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m2 reduced the likelihood of hyperkalemia and other adverse events.
Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.
The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.
The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.
A version of this article first appeared on Medscape.com.
CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.
The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.
After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).
The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).
Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.
The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
Threading the needle
For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.
What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.
“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.
Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.
Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
‘A bright future’
“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.
She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.
“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”
Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.
Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.
Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.
Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.
At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.
The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m2 reduced the likelihood of hyperkalemia and other adverse events.
Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.
The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.
The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.
A version of this article first appeared on Medscape.com.
CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.
The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.
After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).
The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).
Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.
The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
Threading the needle
For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.
What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.
“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.
Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.
Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
‘A bright future’
“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.
She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.
“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”
Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.
Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.
Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.
Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.
At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.
The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m2 reduced the likelihood of hyperkalemia and other adverse events.
Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.
The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.
The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.
A version of this article first appeared on Medscape.com.
AT AHA 2022
Birth method affects microbiome and vaccination response
Babies born vaginally have a different microbiome to those born by Caesarean section and have heightened responses to childhood vaccinations, according to a new study heralded as “interesting and important” by experts.
The microbiome is known to play a role in immune responses to vaccination. However, the relationship between early-life effects on intestinal microbiota composition and subsequent childhood vaccine responses had remained poorly understood. In the new study, “the findings suggest that vaginal birthing resulted in a microbiota composition associated with an increase in a specific type of antibody response to two routine childhood vaccines in healthy babies, compared with Caesarean section,” the authors said.
Researchers from the University of Edinburgh, with colleagues at Spaarne Hospital and University Medical Centre in Utrecht, and the National Institute for Public Health and the Environment in The Netherlands, tracked the development of the gut microbiome in a cohort of 120 healthy, full-term infants and assessed their antibody levels following two common childhood vaccinations.
The study, published in Nature Communications, found “a clear relationship between microbes in the gut of those babies and levels of antibodies.” Not only was vaginal birth associated with increased levels of Bifidobacterium and Escherichia coli in the gut microbiome in the first months of life but also with higher IgG antibody responses against both pneumococcal and meningococcal vaccines.
Antibody responses doubled after vaginal birth
The babies were given pneumococcal and meningococcal vaccinations at 8 and 12 weeks, and saliva was collected at follow-up visits at ages 12 and 18 months for antibody measurement. In the 101 babies tested for pneumococcal antibodies, the researchers found that antibody levels were twice as high among babies delivered naturally, compared with those delivered by C-section. High levels of two gut bacteria in particular – Bifidobacterium and E. coli – were associated with high antibody responses to the pneumococcal vaccine, showing that the microbiome mediated the link between mode of delivery and pneumococcal vaccine responses.
In 66 babies tested for anti-meningococcal antibodies, antibodies were 1.7 times higher for vaginally-born babies than those delivered via C-section, and high antibody levels were particularly associated with high levels of E. coli in the babies’ microbiome.
The results were also influenced by breast-feeding, which even among children born vaginally was linked with 3.5 times higher pneumococcal antibody levels, compared with those of formula-fed children. In contrast, levels of antibodies against meningococcus were unaffected by breast-feeding status.
Microbiome ‘sets level of infection protection’
The team said: “The baby acquires Bifidobacterium and E. coli bacteria through natural birth, and human milk is needed to provide the sugars for these bacteria to thrive on.” They explained: “The gut microbiome is seeded at birth, developing rapidly over the first few months of life, and is influenced mostly by delivery mode, breast-feeding, and antibiotic use.” The babies’ microbiome in early life contributes the immune system’s response to vaccines, they said, “and sets the level of protection against certain infections in childhood.”
Study lead Professor Debby Bogaert, chair of pediatric medicine at the University of Edinburgh, said: “I think it is especially interesting that we identified several beneficial microbes to be the link between mode of delivery and vaccine responses. In the future, we may be able to supplement those bacteria to children born by C-section shortly after birth through – for example, mother-to-baby ‘fecal transplants’ or the use of specifically designed probiotics.”
First author Dr. Emma de Koff, a microbiology trainee at the Amsterdam University Medical Center, said: “We expected to find a link between the gut microbiome and the babies’ vaccine responses, however we never thought to find the strongest effects in the first weeks of life.”
The findings “could help to inform conversations about C-sections between expectant mothers and their doctors,” commented the researchers, who said that they could also “shape the design of more tailored vaccination programs.” For example, in the future, vaccination schedules could be adjusted based on the method of delivery or analysis of the baby’s microbiome.
Potential to rectify immune system after Caesarean
Responding to the study, Professor Neil Mabbott, personal chair in immunopathology at the Roslin Institute of the University of Edinburgh, told the Science Media Centre: “This is a very interesting and important study. The authors show that infants delivered by a vaginal birth had higher responses to the two different types of vaccines against bacterial diseases, and this was associated with higher abundances of the potentially beneficial bacteria known as Bifidobacterium and E. coli in their intestines.”
He added: “This study raises the possibility that it may be possible to treat infants, especially Caesarean-delivered infants, with a bacterial supplement, or even a product produced by these beneficial bacteria, to help improve their immune systems, enhance their responses to certain vaccines and reduce their susceptibility to infections.”
The study raises important questions, he said, including whether the increased antibody levels from pneumococcal and meningococcal vaccinations following vaginal birth also leads to increased protection of the infants against infection or serious disease.
Sheena Cruickshank, immunologist and professor in biomedical sciences at the University of Manchester, England, commented: “It is now well established that the microbiome is important in immune development. In turn the mode of delivery and initial method of feeding is important in how the microbiome is first seeded in the baby.”
“However, other factors such as exposure to antibiotics and subsequent diet also play a role in how it then develops, making understanding the way the microbiome develops and changes quite complex. Microbes works as communities, and it can be difficult to determine whether changes in single species are important functionally. Breast milk also plays an important role in protecting the baby via transfer of maternal immunoglobulins, which will wane over a period of 6-12 months in the baby – thus ascertaining whether it’s the baby’s Ig is challenging.
“Given the complexity of the multitude of interactions, it is important that this is accounted for, and group sizes are large enough to ensure data is robust. Whilst this is an interesting study that adds to our knowledge of how the microbiome develops and the possible implications for immune development, it is still very preliminary, and the small group sizes warrant a need for further studies to verify this in larger groups.”
She added: “We will need to understand whether possible impacts of maternal delivery and feeding on immune development or vaccine responses can be restored by, for example, manipulating the microbiome.”
Professor Kim Barrett, vice dean for research at the University of California, Davis School of Medicine, said that, while further research was needed to uncover if and how manipulation of the human microbiome following C-section births might improve vaccine efficacy, “the work should at least lead to prompt additional consideration about an unintended consequence of the ever-increasing use of C-sections that may not be medically-necessary.”
Dr. Marie Lewis, researcher in gut microbiota at the University of Reading, England, said: “We have known for quite some time that the mode of delivery is incredibly important when it comes to the type of bacteria which colonize our guts. We also know that our gut bacteria in early life drive the development of our immune system, and natural births are linked with reduced risks of developing inflammatory conditions, such as asthma. It is therefore perhaps not really surprising that mode of delivery is also linked to responses to vaccinations.”
“The really interesting part here is the extent to which our gut microbiotas are accessible and changeable, and this important work could pave the way for administration of probiotics and prebiotics to improve vaccine responses in Caesarean-born children.”
‘Tantalizing data’
Dr. Chrissie Jones, associate professor of pediatric infectious diseases at the University of Southampton, and Southampton UK and education lead for the British Paediatric Allergy, Immunity, and Infection Group, said: “The link between method of delivery of the infant and the bacteria that live in the gut of the young infant has previously been shown. What is really interesting about this study is that, for the first time, the link between method of delivery (vaginal delivery vs. C-section), differences in bacterial communities of the gut, and differences in responses to vaccines is shown.”
“This study may give us fresh insights into the differences that we see in the amount of protective antibodies made after infant vaccination. It also gives us clues as to ways that we might be able to level the playing field for infants in the future – for instance, giving babies a safe cocktail of ‘friendly bacteria’ as a probiotic, or an additional dose of vaccine.”
“This study is the first step – it shows us a link or association but does not prove cause and effect that differences in the way babies are born alters how the immune system responds to vaccines. To prove this link we will need larger studies, but it is tantalizing data.”
The research was funded by Scotland’s Chief Scientist Office and the Netherlands Organisation for Scientific Research. DB received funding from OM pharma and Sanofi. All of the authors declared no other conflicts of interest.
A version of this article first appeared on Medscape.com.
Babies born vaginally have a different microbiome to those born by Caesarean section and have heightened responses to childhood vaccinations, according to a new study heralded as “interesting and important” by experts.
The microbiome is known to play a role in immune responses to vaccination. However, the relationship between early-life effects on intestinal microbiota composition and subsequent childhood vaccine responses had remained poorly understood. In the new study, “the findings suggest that vaginal birthing resulted in a microbiota composition associated with an increase in a specific type of antibody response to two routine childhood vaccines in healthy babies, compared with Caesarean section,” the authors said.
Researchers from the University of Edinburgh, with colleagues at Spaarne Hospital and University Medical Centre in Utrecht, and the National Institute for Public Health and the Environment in The Netherlands, tracked the development of the gut microbiome in a cohort of 120 healthy, full-term infants and assessed their antibody levels following two common childhood vaccinations.
The study, published in Nature Communications, found “a clear relationship between microbes in the gut of those babies and levels of antibodies.” Not only was vaginal birth associated with increased levels of Bifidobacterium and Escherichia coli in the gut microbiome in the first months of life but also with higher IgG antibody responses against both pneumococcal and meningococcal vaccines.
Antibody responses doubled after vaginal birth
The babies were given pneumococcal and meningococcal vaccinations at 8 and 12 weeks, and saliva was collected at follow-up visits at ages 12 and 18 months for antibody measurement. In the 101 babies tested for pneumococcal antibodies, the researchers found that antibody levels were twice as high among babies delivered naturally, compared with those delivered by C-section. High levels of two gut bacteria in particular – Bifidobacterium and E. coli – were associated with high antibody responses to the pneumococcal vaccine, showing that the microbiome mediated the link between mode of delivery and pneumococcal vaccine responses.
In 66 babies tested for anti-meningococcal antibodies, antibodies were 1.7 times higher for vaginally-born babies than those delivered via C-section, and high antibody levels were particularly associated with high levels of E. coli in the babies’ microbiome.
The results were also influenced by breast-feeding, which even among children born vaginally was linked with 3.5 times higher pneumococcal antibody levels, compared with those of formula-fed children. In contrast, levels of antibodies against meningococcus were unaffected by breast-feeding status.
Microbiome ‘sets level of infection protection’
The team said: “The baby acquires Bifidobacterium and E. coli bacteria through natural birth, and human milk is needed to provide the sugars for these bacteria to thrive on.” They explained: “The gut microbiome is seeded at birth, developing rapidly over the first few months of life, and is influenced mostly by delivery mode, breast-feeding, and antibiotic use.” The babies’ microbiome in early life contributes the immune system’s response to vaccines, they said, “and sets the level of protection against certain infections in childhood.”
Study lead Professor Debby Bogaert, chair of pediatric medicine at the University of Edinburgh, said: “I think it is especially interesting that we identified several beneficial microbes to be the link between mode of delivery and vaccine responses. In the future, we may be able to supplement those bacteria to children born by C-section shortly after birth through – for example, mother-to-baby ‘fecal transplants’ or the use of specifically designed probiotics.”
First author Dr. Emma de Koff, a microbiology trainee at the Amsterdam University Medical Center, said: “We expected to find a link between the gut microbiome and the babies’ vaccine responses, however we never thought to find the strongest effects in the first weeks of life.”
The findings “could help to inform conversations about C-sections between expectant mothers and their doctors,” commented the researchers, who said that they could also “shape the design of more tailored vaccination programs.” For example, in the future, vaccination schedules could be adjusted based on the method of delivery or analysis of the baby’s microbiome.
Potential to rectify immune system after Caesarean
Responding to the study, Professor Neil Mabbott, personal chair in immunopathology at the Roslin Institute of the University of Edinburgh, told the Science Media Centre: “This is a very interesting and important study. The authors show that infants delivered by a vaginal birth had higher responses to the two different types of vaccines against bacterial diseases, and this was associated with higher abundances of the potentially beneficial bacteria known as Bifidobacterium and E. coli in their intestines.”
He added: “This study raises the possibility that it may be possible to treat infants, especially Caesarean-delivered infants, with a bacterial supplement, or even a product produced by these beneficial bacteria, to help improve their immune systems, enhance their responses to certain vaccines and reduce their susceptibility to infections.”
The study raises important questions, he said, including whether the increased antibody levels from pneumococcal and meningococcal vaccinations following vaginal birth also leads to increased protection of the infants against infection or serious disease.
Sheena Cruickshank, immunologist and professor in biomedical sciences at the University of Manchester, England, commented: “It is now well established that the microbiome is important in immune development. In turn the mode of delivery and initial method of feeding is important in how the microbiome is first seeded in the baby.”
“However, other factors such as exposure to antibiotics and subsequent diet also play a role in how it then develops, making understanding the way the microbiome develops and changes quite complex. Microbes works as communities, and it can be difficult to determine whether changes in single species are important functionally. Breast milk also plays an important role in protecting the baby via transfer of maternal immunoglobulins, which will wane over a period of 6-12 months in the baby – thus ascertaining whether it’s the baby’s Ig is challenging.
“Given the complexity of the multitude of interactions, it is important that this is accounted for, and group sizes are large enough to ensure data is robust. Whilst this is an interesting study that adds to our knowledge of how the microbiome develops and the possible implications for immune development, it is still very preliminary, and the small group sizes warrant a need for further studies to verify this in larger groups.”
She added: “We will need to understand whether possible impacts of maternal delivery and feeding on immune development or vaccine responses can be restored by, for example, manipulating the microbiome.”
Professor Kim Barrett, vice dean for research at the University of California, Davis School of Medicine, said that, while further research was needed to uncover if and how manipulation of the human microbiome following C-section births might improve vaccine efficacy, “the work should at least lead to prompt additional consideration about an unintended consequence of the ever-increasing use of C-sections that may not be medically-necessary.”
Dr. Marie Lewis, researcher in gut microbiota at the University of Reading, England, said: “We have known for quite some time that the mode of delivery is incredibly important when it comes to the type of bacteria which colonize our guts. We also know that our gut bacteria in early life drive the development of our immune system, and natural births are linked with reduced risks of developing inflammatory conditions, such as asthma. It is therefore perhaps not really surprising that mode of delivery is also linked to responses to vaccinations.”
“The really interesting part here is the extent to which our gut microbiotas are accessible and changeable, and this important work could pave the way for administration of probiotics and prebiotics to improve vaccine responses in Caesarean-born children.”
‘Tantalizing data’
Dr. Chrissie Jones, associate professor of pediatric infectious diseases at the University of Southampton, and Southampton UK and education lead for the British Paediatric Allergy, Immunity, and Infection Group, said: “The link between method of delivery of the infant and the bacteria that live in the gut of the young infant has previously been shown. What is really interesting about this study is that, for the first time, the link between method of delivery (vaginal delivery vs. C-section), differences in bacterial communities of the gut, and differences in responses to vaccines is shown.”
“This study may give us fresh insights into the differences that we see in the amount of protective antibodies made after infant vaccination. It also gives us clues as to ways that we might be able to level the playing field for infants in the future – for instance, giving babies a safe cocktail of ‘friendly bacteria’ as a probiotic, or an additional dose of vaccine.”
“This study is the first step – it shows us a link or association but does not prove cause and effect that differences in the way babies are born alters how the immune system responds to vaccines. To prove this link we will need larger studies, but it is tantalizing data.”
The research was funded by Scotland’s Chief Scientist Office and the Netherlands Organisation for Scientific Research. DB received funding from OM pharma and Sanofi. All of the authors declared no other conflicts of interest.
A version of this article first appeared on Medscape.com.
Babies born vaginally have a different microbiome to those born by Caesarean section and have heightened responses to childhood vaccinations, according to a new study heralded as “interesting and important” by experts.
The microbiome is known to play a role in immune responses to vaccination. However, the relationship between early-life effects on intestinal microbiota composition and subsequent childhood vaccine responses had remained poorly understood. In the new study, “the findings suggest that vaginal birthing resulted in a microbiota composition associated with an increase in a specific type of antibody response to two routine childhood vaccines in healthy babies, compared with Caesarean section,” the authors said.
Researchers from the University of Edinburgh, with colleagues at Spaarne Hospital and University Medical Centre in Utrecht, and the National Institute for Public Health and the Environment in The Netherlands, tracked the development of the gut microbiome in a cohort of 120 healthy, full-term infants and assessed their antibody levels following two common childhood vaccinations.
The study, published in Nature Communications, found “a clear relationship between microbes in the gut of those babies and levels of antibodies.” Not only was vaginal birth associated with increased levels of Bifidobacterium and Escherichia coli in the gut microbiome in the first months of life but also with higher IgG antibody responses against both pneumococcal and meningococcal vaccines.
Antibody responses doubled after vaginal birth
The babies were given pneumococcal and meningococcal vaccinations at 8 and 12 weeks, and saliva was collected at follow-up visits at ages 12 and 18 months for antibody measurement. In the 101 babies tested for pneumococcal antibodies, the researchers found that antibody levels were twice as high among babies delivered naturally, compared with those delivered by C-section. High levels of two gut bacteria in particular – Bifidobacterium and E. coli – were associated with high antibody responses to the pneumococcal vaccine, showing that the microbiome mediated the link between mode of delivery and pneumococcal vaccine responses.
In 66 babies tested for anti-meningococcal antibodies, antibodies were 1.7 times higher for vaginally-born babies than those delivered via C-section, and high antibody levels were particularly associated with high levels of E. coli in the babies’ microbiome.
The results were also influenced by breast-feeding, which even among children born vaginally was linked with 3.5 times higher pneumococcal antibody levels, compared with those of formula-fed children. In contrast, levels of antibodies against meningococcus were unaffected by breast-feeding status.
Microbiome ‘sets level of infection protection’
The team said: “The baby acquires Bifidobacterium and E. coli bacteria through natural birth, and human milk is needed to provide the sugars for these bacteria to thrive on.” They explained: “The gut microbiome is seeded at birth, developing rapidly over the first few months of life, and is influenced mostly by delivery mode, breast-feeding, and antibiotic use.” The babies’ microbiome in early life contributes the immune system’s response to vaccines, they said, “and sets the level of protection against certain infections in childhood.”
Study lead Professor Debby Bogaert, chair of pediatric medicine at the University of Edinburgh, said: “I think it is especially interesting that we identified several beneficial microbes to be the link between mode of delivery and vaccine responses. In the future, we may be able to supplement those bacteria to children born by C-section shortly after birth through – for example, mother-to-baby ‘fecal transplants’ or the use of specifically designed probiotics.”
First author Dr. Emma de Koff, a microbiology trainee at the Amsterdam University Medical Center, said: “We expected to find a link between the gut microbiome and the babies’ vaccine responses, however we never thought to find the strongest effects in the first weeks of life.”
The findings “could help to inform conversations about C-sections between expectant mothers and their doctors,” commented the researchers, who said that they could also “shape the design of more tailored vaccination programs.” For example, in the future, vaccination schedules could be adjusted based on the method of delivery or analysis of the baby’s microbiome.
Potential to rectify immune system after Caesarean
Responding to the study, Professor Neil Mabbott, personal chair in immunopathology at the Roslin Institute of the University of Edinburgh, told the Science Media Centre: “This is a very interesting and important study. The authors show that infants delivered by a vaginal birth had higher responses to the two different types of vaccines against bacterial diseases, and this was associated with higher abundances of the potentially beneficial bacteria known as Bifidobacterium and E. coli in their intestines.”
He added: “This study raises the possibility that it may be possible to treat infants, especially Caesarean-delivered infants, with a bacterial supplement, or even a product produced by these beneficial bacteria, to help improve their immune systems, enhance their responses to certain vaccines and reduce their susceptibility to infections.”
The study raises important questions, he said, including whether the increased antibody levels from pneumococcal and meningococcal vaccinations following vaginal birth also leads to increased protection of the infants against infection or serious disease.
Sheena Cruickshank, immunologist and professor in biomedical sciences at the University of Manchester, England, commented: “It is now well established that the microbiome is important in immune development. In turn the mode of delivery and initial method of feeding is important in how the microbiome is first seeded in the baby.”
“However, other factors such as exposure to antibiotics and subsequent diet also play a role in how it then develops, making understanding the way the microbiome develops and changes quite complex. Microbes works as communities, and it can be difficult to determine whether changes in single species are important functionally. Breast milk also plays an important role in protecting the baby via transfer of maternal immunoglobulins, which will wane over a period of 6-12 months in the baby – thus ascertaining whether it’s the baby’s Ig is challenging.
“Given the complexity of the multitude of interactions, it is important that this is accounted for, and group sizes are large enough to ensure data is robust. Whilst this is an interesting study that adds to our knowledge of how the microbiome develops and the possible implications for immune development, it is still very preliminary, and the small group sizes warrant a need for further studies to verify this in larger groups.”
She added: “We will need to understand whether possible impacts of maternal delivery and feeding on immune development or vaccine responses can be restored by, for example, manipulating the microbiome.”
Professor Kim Barrett, vice dean for research at the University of California, Davis School of Medicine, said that, while further research was needed to uncover if and how manipulation of the human microbiome following C-section births might improve vaccine efficacy, “the work should at least lead to prompt additional consideration about an unintended consequence of the ever-increasing use of C-sections that may not be medically-necessary.”
Dr. Marie Lewis, researcher in gut microbiota at the University of Reading, England, said: “We have known for quite some time that the mode of delivery is incredibly important when it comes to the type of bacteria which colonize our guts. We also know that our gut bacteria in early life drive the development of our immune system, and natural births are linked with reduced risks of developing inflammatory conditions, such as asthma. It is therefore perhaps not really surprising that mode of delivery is also linked to responses to vaccinations.”
“The really interesting part here is the extent to which our gut microbiotas are accessible and changeable, and this important work could pave the way for administration of probiotics and prebiotics to improve vaccine responses in Caesarean-born children.”
‘Tantalizing data’
Dr. Chrissie Jones, associate professor of pediatric infectious diseases at the University of Southampton, and Southampton UK and education lead for the British Paediatric Allergy, Immunity, and Infection Group, said: “The link between method of delivery of the infant and the bacteria that live in the gut of the young infant has previously been shown. What is really interesting about this study is that, for the first time, the link between method of delivery (vaginal delivery vs. C-section), differences in bacterial communities of the gut, and differences in responses to vaccines is shown.”
“This study may give us fresh insights into the differences that we see in the amount of protective antibodies made after infant vaccination. It also gives us clues as to ways that we might be able to level the playing field for infants in the future – for instance, giving babies a safe cocktail of ‘friendly bacteria’ as a probiotic, or an additional dose of vaccine.”
“This study is the first step – it shows us a link or association but does not prove cause and effect that differences in the way babies are born alters how the immune system responds to vaccines. To prove this link we will need larger studies, but it is tantalizing data.”
The research was funded by Scotland’s Chief Scientist Office and the Netherlands Organisation for Scientific Research. DB received funding from OM pharma and Sanofi. All of the authors declared no other conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM NATURE COMMUNICATIONS
Update on high-grade vulvar interepithelial neoplasia
Vulvar squamous cell carcinomas (VSCC) comprise approximately 90% of all vulvar malignancies. Unlike cervical SCC, which are predominantly human papilloma virus (HPV) positive, only a minority of VSCC are HPV positive – on the order of 15%-25% of cases. Most cases occur in the setting of lichen sclerosus and are HPV negative.
Lichen sclerosus is a chronic inflammatory dermatitis typically involving the anogenital area, which in some cases can become seriously distorted (e.g. atrophy of the labia minora, clitoral phimosis, and introital stenosis). Although most cases are diagnosed in postmenopausal women, LS can affect women of any age. The true prevalence of lichen sclerosus is unknown. Recent studies have shown a prevalence of 1 in 60; among older women, it can even be as high as 1 in 30. While lichen sclerosus is a pruriginous condition, it is often asymptomatic. It is not considered a premalignant condition. The diagnosis is clinical; however, suspicious lesions (erosions/ulcerations, hyperkeratosis, pigmented areas, ecchymosis, warty or papular lesions), particularly when recalcitrant to adequate first-line therapy, should be biopsied.
VSCC arises from precursor lesions or high-grade vulvar intraepithelial neoplasia (VIN). The 2015 International Society for the Study of Vulvovaginal Disease nomenclature classifies high-grade VIN into high-grade squamous intraepithelial lesion (HSIL) and differentiated VIN (dVIN). Most patients with high-grade VIN are diagnosed with HSIL or usual type VIN. A preponderance of these lesions (75%-85%) are HPV positive, predominantly HPV 16. Vulvar HSIL (vHSIL) lesions affect younger women. The lesions tend to be multifocal and extensive. On the other hand, dVIN typically affects older women and commonly develops as a solitary lesion. While dVIN accounts for only a small subset of patients with high-grade VIN, these lesions are HPV negative and associated with lichen sclerosus.
Both disease entities, vHSIL and dVIN, are increasing in incidence. There is a higher risk and shortened period of progression to cancer in patients with dVIN compared to HSIL. The cancer risk of vHSIL is relatively low. The 10-year cumulative VSCC risk reported in the literature is 10.3%; 9.7% for vHSIL and 50% for dVIN. Patients with vHSIL could benefit from less aggressive treatment modalities.
Patients present with a constellation of signs such as itching, pain, burning, bleeding, and discharge. Chronic symptoms portend HPV-independent lesions associated with lichen sclerosus while episodic signs are suggestive of HPV-positive lesions.
The recurrence risk of high-grade VIN is 46%-70%. Risk factors for recurrence include age greater than 50, immunosuppression, metasynchronous HSIL, and multifocal lesions. Recurrences occur in up to 50% of women who have undergone surgery. For those who undergo surgical treatment for high-grade VIN, recurrence is more common in the setting of positive margins, underlying lichen sclerosis, persistent HPV infection, and immunosuppression.
Management of high-grade VIN is determined by the lesion characteristics, patient characteristics, and medical expertise. Given the risk of progression of high-grade VIN to cancer and risk of underlying cancer, surgical therapy is typically recommended. The treatment of choice is surgical excision in cases of dVIN. Surgical treatments include CO2 laser ablation, wide local excision, and vulvectomy. Women who undergo surgical treatment for vHSIL have about a 50% chance of the condition recurring 1 year later, irrespective of whether treatment is by surgical excision or laser vaporization.
Since surgery can be associated with disfigurement and sexual dysfunction, alternatives to surgery should be considered in cases of vHSIL. The potential for effect on sexual function should be part of preoperative counseling and treatment. Women treated for VIN often experience increased inhibition of sexual excitement and increased inhibition of orgasm. One study found that in women undergoing vulvar excision for VIN, the impairment was found to be psychological in nature. Overall, the studies of sexual effect from treatment of VIN have found that women do not return to their pretreatment sexual function. However, the optimal management of vHSIL has not been determined. Nonsurgical options include topical therapies (imiquimod, 5-fluorouracil, cidofovir, and interferon) and nonpharmacologic treatments, such as photodynamic therapy.
Imiquimod, a topical immune modulator, is the most studied pharmacologic treatment of vHSIL. The drug induces secretion of cytokines, creating an immune response that clears the HPV infection. Imiquimod is safe and well tolerated. The clinical response rate varies between 35% and 81%. A recent study demonstrated the efficacy of imiquimod and the treatment was found to be noninferior to surgery. Adverse events differed, with local pain following surgical treatment and local pruritus and erythema associated with imiquimod use. Some patients did not respond to imiquimod; it was thought by the authors of the study that specific immunological factors affect the clinical response. 
In conclusion, high-grade VIN is a heterogeneous disease made up of two distinct disease entities with rising incidence. In contrast to dVIN, the cancer risk is low for patients with vHSIL. Treatment should be driven by the clinical characteristics of the vulvar lesions, patients’ preferences, sexual activity, and compliance. Future directions include risk stratification of patients with vHSIL who are most likely to benefit from topical treatments, thus reducing overtreatment. Molecular biomarkers that could identify dVIN at an early stage are needed.
Dr. Jackson-Moore is associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.
References
Cendejas BR et al. Am J Obstet Gynecol. 2015 Mar;212(3):291-7.
Lebreton M et al. J Gynecol Obstet Hum Reprod. 2020 Nov;49(9):101801.
Thuijs NB et al. Int J Cancer. 2021 Jan 1;148(1):90-8. doi: 10.1002/ijc.33198. .
Trutnovsky G et al. Lancet. 2022 May 7;399(10337):1790-8. Erratum in: Lancet. 2022 Oct 8;400(10359):1194.
Vulvar squamous cell carcinomas (VSCC) comprise approximately 90% of all vulvar malignancies. Unlike cervical SCC, which are predominantly human papilloma virus (HPV) positive, only a minority of VSCC are HPV positive – on the order of 15%-25% of cases. Most cases occur in the setting of lichen sclerosus and are HPV negative.
Lichen sclerosus is a chronic inflammatory dermatitis typically involving the anogenital area, which in some cases can become seriously distorted (e.g. atrophy of the labia minora, clitoral phimosis, and introital stenosis). Although most cases are diagnosed in postmenopausal women, LS can affect women of any age. The true prevalence of lichen sclerosus is unknown. Recent studies have shown a prevalence of 1 in 60; among older women, it can even be as high as 1 in 30. While lichen sclerosus is a pruriginous condition, it is often asymptomatic. It is not considered a premalignant condition. The diagnosis is clinical; however, suspicious lesions (erosions/ulcerations, hyperkeratosis, pigmented areas, ecchymosis, warty or papular lesions), particularly when recalcitrant to adequate first-line therapy, should be biopsied.
VSCC arises from precursor lesions or high-grade vulvar intraepithelial neoplasia (VIN). The 2015 International Society for the Study of Vulvovaginal Disease nomenclature classifies high-grade VIN into high-grade squamous intraepithelial lesion (HSIL) and differentiated VIN (dVIN). Most patients with high-grade VIN are diagnosed with HSIL or usual type VIN. A preponderance of these lesions (75%-85%) are HPV positive, predominantly HPV 16. Vulvar HSIL (vHSIL) lesions affect younger women. The lesions tend to be multifocal and extensive. On the other hand, dVIN typically affects older women and commonly develops as a solitary lesion. While dVIN accounts for only a small subset of patients with high-grade VIN, these lesions are HPV negative and associated with lichen sclerosus.
Both disease entities, vHSIL and dVIN, are increasing in incidence. There is a higher risk and shortened period of progression to cancer in patients with dVIN compared to HSIL. The cancer risk of vHSIL is relatively low. The 10-year cumulative VSCC risk reported in the literature is 10.3%; 9.7% for vHSIL and 50% for dVIN. Patients with vHSIL could benefit from less aggressive treatment modalities.
Patients present with a constellation of signs such as itching, pain, burning, bleeding, and discharge. Chronic symptoms portend HPV-independent lesions associated with lichen sclerosus while episodic signs are suggestive of HPV-positive lesions.
The recurrence risk of high-grade VIN is 46%-70%. Risk factors for recurrence include age greater than 50, immunosuppression, metasynchronous HSIL, and multifocal lesions. Recurrences occur in up to 50% of women who have undergone surgery. For those who undergo surgical treatment for high-grade VIN, recurrence is more common in the setting of positive margins, underlying lichen sclerosis, persistent HPV infection, and immunosuppression.
Management of high-grade VIN is determined by the lesion characteristics, patient characteristics, and medical expertise. Given the risk of progression of high-grade VIN to cancer and risk of underlying cancer, surgical therapy is typically recommended. The treatment of choice is surgical excision in cases of dVIN. Surgical treatments include CO2 laser ablation, wide local excision, and vulvectomy. Women who undergo surgical treatment for vHSIL have about a 50% chance of the condition recurring 1 year later, irrespective of whether treatment is by surgical excision or laser vaporization.
Since surgery can be associated with disfigurement and sexual dysfunction, alternatives to surgery should be considered in cases of vHSIL. The potential for effect on sexual function should be part of preoperative counseling and treatment. Women treated for VIN often experience increased inhibition of sexual excitement and increased inhibition of orgasm. One study found that in women undergoing vulvar excision for VIN, the impairment was found to be psychological in nature. Overall, the studies of sexual effect from treatment of VIN have found that women do not return to their pretreatment sexual function. However, the optimal management of vHSIL has not been determined. Nonsurgical options include topical therapies (imiquimod, 5-fluorouracil, cidofovir, and interferon) and nonpharmacologic treatments, such as photodynamic therapy.
Imiquimod, a topical immune modulator, is the most studied pharmacologic treatment of vHSIL. The drug induces secretion of cytokines, creating an immune response that clears the HPV infection. Imiquimod is safe and well tolerated. The clinical response rate varies between 35% and 81%. A recent study demonstrated the efficacy of imiquimod and the treatment was found to be noninferior to surgery. Adverse events differed, with local pain following surgical treatment and local pruritus and erythema associated with imiquimod use. Some patients did not respond to imiquimod; it was thought by the authors of the study that specific immunological factors affect the clinical response.
In conclusion, high-grade VIN is a heterogeneous disease made up of two distinct disease entities with rising incidence. In contrast to dVIN, the cancer risk is low for patients with vHSIL. Treatment should be driven by the clinical characteristics of the vulvar lesions, patients’ preferences, sexual activity, and compliance. Future directions include risk stratification of patients with vHSIL who are most likely to benefit from topical treatments, thus reducing overtreatment. Molecular biomarkers that could identify dVIN at an early stage are needed.
Dr. Jackson-Moore is associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.
References
Cendejas BR et al. Am J Obstet Gynecol. 2015 Mar;212(3):291-7.
Lebreton M et al. J Gynecol Obstet Hum Reprod. 2020 Nov;49(9):101801.
Thuijs NB et al. Int J Cancer. 2021 Jan 1;148(1):90-8. doi: 10.1002/ijc.33198. .
Trutnovsky G et al. Lancet. 2022 May 7;399(10337):1790-8. Erratum in: Lancet. 2022 Oct 8;400(10359):1194.
Vulvar squamous cell carcinomas (VSCC) comprise approximately 90% of all vulvar malignancies. Unlike cervical SCC, which are predominantly human papilloma virus (HPV) positive, only a minority of VSCC are HPV positive – on the order of 15%-25% of cases. Most cases occur in the setting of lichen sclerosus and are HPV negative.
Lichen sclerosus is a chronic inflammatory dermatitis typically involving the anogenital area, which in some cases can become seriously distorted (e.g. atrophy of the labia minora, clitoral phimosis, and introital stenosis). Although most cases are diagnosed in postmenopausal women, LS can affect women of any age. The true prevalence of lichen sclerosus is unknown. Recent studies have shown a prevalence of 1 in 60; among older women, it can even be as high as 1 in 30. While lichen sclerosus is a pruriginous condition, it is often asymptomatic. It is not considered a premalignant condition. The diagnosis is clinical; however, suspicious lesions (erosions/ulcerations, hyperkeratosis, pigmented areas, ecchymosis, warty or papular lesions), particularly when recalcitrant to adequate first-line therapy, should be biopsied.
VSCC arises from precursor lesions or high-grade vulvar intraepithelial neoplasia (VIN). The 2015 International Society for the Study of Vulvovaginal Disease nomenclature classifies high-grade VIN into high-grade squamous intraepithelial lesion (HSIL) and differentiated VIN (dVIN). Most patients with high-grade VIN are diagnosed with HSIL or usual type VIN. A preponderance of these lesions (75%-85%) are HPV positive, predominantly HPV 16. Vulvar HSIL (vHSIL) lesions affect younger women. The lesions tend to be multifocal and extensive. On the other hand, dVIN typically affects older women and commonly develops as a solitary lesion. While dVIN accounts for only a small subset of patients with high-grade VIN, these lesions are HPV negative and associated with lichen sclerosus.
Both disease entities, vHSIL and dVIN, are increasing in incidence. There is a higher risk and shortened period of progression to cancer in patients with dVIN compared to HSIL. The cancer risk of vHSIL is relatively low. The 10-year cumulative VSCC risk reported in the literature is 10.3%; 9.7% for vHSIL and 50% for dVIN. Patients with vHSIL could benefit from less aggressive treatment modalities.
Patients present with a constellation of signs such as itching, pain, burning, bleeding, and discharge. Chronic symptoms portend HPV-independent lesions associated with lichen sclerosus while episodic signs are suggestive of HPV-positive lesions.
The recurrence risk of high-grade VIN is 46%-70%. Risk factors for recurrence include age greater than 50, immunosuppression, metasynchronous HSIL, and multifocal lesions. Recurrences occur in up to 50% of women who have undergone surgery. For those who undergo surgical treatment for high-grade VIN, recurrence is more common in the setting of positive margins, underlying lichen sclerosis, persistent HPV infection, and immunosuppression.
Management of high-grade VIN is determined by the lesion characteristics, patient characteristics, and medical expertise. Given the risk of progression of high-grade VIN to cancer and risk of underlying cancer, surgical therapy is typically recommended. The treatment of choice is surgical excision in cases of dVIN. Surgical treatments include CO2 laser ablation, wide local excision, and vulvectomy. Women who undergo surgical treatment for vHSIL have about a 50% chance of the condition recurring 1 year later, irrespective of whether treatment is by surgical excision or laser vaporization.
Since surgery can be associated with disfigurement and sexual dysfunction, alternatives to surgery should be considered in cases of vHSIL. The potential for effect on sexual function should be part of preoperative counseling and treatment. Women treated for VIN often experience increased inhibition of sexual excitement and increased inhibition of orgasm. One study found that in women undergoing vulvar excision for VIN, the impairment was found to be psychological in nature. Overall, the studies of sexual effect from treatment of VIN have found that women do not return to their pretreatment sexual function. However, the optimal management of vHSIL has not been determined. Nonsurgical options include topical therapies (imiquimod, 5-fluorouracil, cidofovir, and interferon) and nonpharmacologic treatments, such as photodynamic therapy.
Imiquimod, a topical immune modulator, is the most studied pharmacologic treatment of vHSIL. The drug induces secretion of cytokines, creating an immune response that clears the HPV infection. Imiquimod is safe and well tolerated. The clinical response rate varies between 35% and 81%. A recent study demonstrated the efficacy of imiquimod and the treatment was found to be noninferior to surgery. Adverse events differed, with local pain following surgical treatment and local pruritus and erythema associated with imiquimod use. Some patients did not respond to imiquimod; it was thought by the authors of the study that specific immunological factors affect the clinical response.
In conclusion, high-grade VIN is a heterogeneous disease made up of two distinct disease entities with rising incidence. In contrast to dVIN, the cancer risk is low for patients with vHSIL. Treatment should be driven by the clinical characteristics of the vulvar lesions, patients’ preferences, sexual activity, and compliance. Future directions include risk stratification of patients with vHSIL who are most likely to benefit from topical treatments, thus reducing overtreatment. Molecular biomarkers that could identify dVIN at an early stage are needed.
Dr. Jackson-Moore is associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.
References
Cendejas BR et al. Am J Obstet Gynecol. 2015 Mar;212(3):291-7.
Lebreton M et al. J Gynecol Obstet Hum Reprod. 2020 Nov;49(9):101801.
Thuijs NB et al. Int J Cancer. 2021 Jan 1;148(1):90-8. doi: 10.1002/ijc.33198. .
Trutnovsky G et al. Lancet. 2022 May 7;399(10337):1790-8. Erratum in: Lancet. 2022 Oct 8;400(10359):1194.
FDA approves first-ever agent to delay type 1 diabetes onset
“Today’s approval of a first-in-class therapy adds an important new treatment option for certain at-risk patients,” said John Sharretts, MD, director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research. “The drug’s potential to delay clinical diagnosis of type 1 diabetes may provide patients with months to years without the burdens of disease.”
The agent, which interferes with T-cell-mediated autoimmune destruction of pancreatic beta cells, is the first disease-modifying therapy for impeding progression of type 1 diabetes. It is administered by intravenous infusion once daily for 14 consecutive days.
The specific indication is “to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes.” In type 1 diabetes staging, adopted in 2015, stage 1 is defined as the presence of beta cell autoimmunity with two or more islet autoantibodies with normoglycemia, stage 2 is beta-cell autoimmunity with dysglycemia yet asymptomatic, and stage 3 is the onset of symptomatic type 1 diabetes.
Stage 2 type 1 diabetes is associated with a nearly 100% lifetime risk of progression to clinical (stage 3) type 1 diabetes and a 75% risk of developing the condition within 5 years.
The FDA had previously rejected teplizumab for this indication in July 2021, despite a prior endorsement from an advisory panel in May 2021.
Now, with the FDA approval, Provention Bio cofounder and CEO Ashleigh Palmer said in a statement, “This is a historic occasion for the T1D community and a paradigm shifting breakthrough ... It cannot be emphasized enough how precious a delay in the onset of stage 3 T1D can be from a patient and family perspective; more time to live without and, when necessary, prepare for the burdens, complications, and risks associated with stage 3 disease.”
T1D onset delayed by 2 years
In 2019, a pivotal phase 2, randomized, placebo-controlled trial involving 76 at-risk children and adults aged 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes compared with 32 who received placebo.
Those “game changer” data were presented at the American Diabetes Association (ADA) annual meeting in June 2019 and simultaneously published in the New England Journal of Medicine.
Three-year data were presented at the June 2020 ADA meeting and published in March 2021 in Science Translational Medicine, by Emily K. Sims, MD, department of pediatrics, Indiana University, Indianapolis, and colleagues.
At a median follow-up of 923 days, 50% of those randomly assigned to teplizumab remained diabetes free, compared with 22% of those who received placebo infusions (hazard ratio, 0.457; P = .01). The teplizumab group had a greater average C-peptide area under the curve compared with placebo, reflecting improved beta-cell function (1.96 vs. 1.68 pmol/mL; P = .006).
C-peptide levels declined over time in the placebo group but stabilized in those receiving teplizumab (P = .0015).
“The mid-range time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for the patients who received Tzield and 25 months for those who received a placebo. This represents a statistically significant delay in the development of stage 3 type 1 diabetes,” according to the FDA statement.
The most common side effects of Tzield include lymphopenia (73% teplizumab vs. 6% placebo), rash (36% vs. 0%), leukopenia (221% vs. 0%), and headache (11% vs. 6%). Label warnings and precautions include monitoring for cytokine release syndrome, risk for serious infections, and avoidance of live, inactivated, and mRNA vaccines.
This approval is likely to accelerate discussion about universal autoantibody screening. Currently, most individuals identified as having preclinical type 1 diabetes are first-degree relatives of people with type 1 diabetes identified through the federally funded TrialNet program. In December 2020, the type 1 diabetes research and advocacy organization JDRF began offering a $55 home blood test to screen for the antibodies, and other screening programs have been launched in the United States and Europe.
Previous studies have examined cost-effectiveness of universal screening in children and the optimal ages that such screening should take place.
In October, Provention Bio announced a co-promotion agreement with Sanofi for the U.S. launch of Tzield for delay in onset of clinical T1D in at-risk individuals. Provention Bio offers financial assistance options (e.g., copay assistance) to eligible patients for out-of-pocket costs.
A version of this article first appeared on Medscape.com.
“Today’s approval of a first-in-class therapy adds an important new treatment option for certain at-risk patients,” said John Sharretts, MD, director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research. “The drug’s potential to delay clinical diagnosis of type 1 diabetes may provide patients with months to years without the burdens of disease.”
The agent, which interferes with T-cell-mediated autoimmune destruction of pancreatic beta cells, is the first disease-modifying therapy for impeding progression of type 1 diabetes. It is administered by intravenous infusion once daily for 14 consecutive days.
The specific indication is “to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes.” In type 1 diabetes staging, adopted in 2015, stage 1 is defined as the presence of beta cell autoimmunity with two or more islet autoantibodies with normoglycemia, stage 2 is beta-cell autoimmunity with dysglycemia yet asymptomatic, and stage 3 is the onset of symptomatic type 1 diabetes.
Stage 2 type 1 diabetes is associated with a nearly 100% lifetime risk of progression to clinical (stage 3) type 1 diabetes and a 75% risk of developing the condition within 5 years.
The FDA had previously rejected teplizumab for this indication in July 2021, despite a prior endorsement from an advisory panel in May 2021.
Now, with the FDA approval, Provention Bio cofounder and CEO Ashleigh Palmer said in a statement, “This is a historic occasion for the T1D community and a paradigm shifting breakthrough ... It cannot be emphasized enough how precious a delay in the onset of stage 3 T1D can be from a patient and family perspective; more time to live without and, when necessary, prepare for the burdens, complications, and risks associated with stage 3 disease.”
T1D onset delayed by 2 years
In 2019, a pivotal phase 2, randomized, placebo-controlled trial involving 76 at-risk children and adults aged 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes compared with 32 who received placebo.
Those “game changer” data were presented at the American Diabetes Association (ADA) annual meeting in June 2019 and simultaneously published in the New England Journal of Medicine.
Three-year data were presented at the June 2020 ADA meeting and published in March 2021 in Science Translational Medicine, by Emily K. Sims, MD, department of pediatrics, Indiana University, Indianapolis, and colleagues.
At a median follow-up of 923 days, 50% of those randomly assigned to teplizumab remained diabetes free, compared with 22% of those who received placebo infusions (hazard ratio, 0.457; P = .01). The teplizumab group had a greater average C-peptide area under the curve compared with placebo, reflecting improved beta-cell function (1.96 vs. 1.68 pmol/mL; P = .006).
C-peptide levels declined over time in the placebo group but stabilized in those receiving teplizumab (P = .0015).
“The mid-range time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for the patients who received Tzield and 25 months for those who received a placebo. This represents a statistically significant delay in the development of stage 3 type 1 diabetes,” according to the FDA statement.
The most common side effects of Tzield include lymphopenia (73% teplizumab vs. 6% placebo), rash (36% vs. 0%), leukopenia (221% vs. 0%), and headache (11% vs. 6%). Label warnings and precautions include monitoring for cytokine release syndrome, risk for serious infections, and avoidance of live, inactivated, and mRNA vaccines.
This approval is likely to accelerate discussion about universal autoantibody screening. Currently, most individuals identified as having preclinical type 1 diabetes are first-degree relatives of people with type 1 diabetes identified through the federally funded TrialNet program. In December 2020, the type 1 diabetes research and advocacy organization JDRF began offering a $55 home blood test to screen for the antibodies, and other screening programs have been launched in the United States and Europe.
Previous studies have examined cost-effectiveness of universal screening in children and the optimal ages that such screening should take place.
In October, Provention Bio announced a co-promotion agreement with Sanofi for the U.S. launch of Tzield for delay in onset of clinical T1D in at-risk individuals. Provention Bio offers financial assistance options (e.g., copay assistance) to eligible patients for out-of-pocket costs.
A version of this article first appeared on Medscape.com.
“Today’s approval of a first-in-class therapy adds an important new treatment option for certain at-risk patients,” said John Sharretts, MD, director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research. “The drug’s potential to delay clinical diagnosis of type 1 diabetes may provide patients with months to years without the burdens of disease.”
The agent, which interferes with T-cell-mediated autoimmune destruction of pancreatic beta cells, is the first disease-modifying therapy for impeding progression of type 1 diabetes. It is administered by intravenous infusion once daily for 14 consecutive days.
The specific indication is “to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes.” In type 1 diabetes staging, adopted in 2015, stage 1 is defined as the presence of beta cell autoimmunity with two or more islet autoantibodies with normoglycemia, stage 2 is beta-cell autoimmunity with dysglycemia yet asymptomatic, and stage 3 is the onset of symptomatic type 1 diabetes.
Stage 2 type 1 diabetes is associated with a nearly 100% lifetime risk of progression to clinical (stage 3) type 1 diabetes and a 75% risk of developing the condition within 5 years.
The FDA had previously rejected teplizumab for this indication in July 2021, despite a prior endorsement from an advisory panel in May 2021.
Now, with the FDA approval, Provention Bio cofounder and CEO Ashleigh Palmer said in a statement, “This is a historic occasion for the T1D community and a paradigm shifting breakthrough ... It cannot be emphasized enough how precious a delay in the onset of stage 3 T1D can be from a patient and family perspective; more time to live without and, when necessary, prepare for the burdens, complications, and risks associated with stage 3 disease.”
T1D onset delayed by 2 years
In 2019, a pivotal phase 2, randomized, placebo-controlled trial involving 76 at-risk children and adults aged 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes compared with 32 who received placebo.
Those “game changer” data were presented at the American Diabetes Association (ADA) annual meeting in June 2019 and simultaneously published in the New England Journal of Medicine.
Three-year data were presented at the June 2020 ADA meeting and published in March 2021 in Science Translational Medicine, by Emily K. Sims, MD, department of pediatrics, Indiana University, Indianapolis, and colleagues.
At a median follow-up of 923 days, 50% of those randomly assigned to teplizumab remained diabetes free, compared with 22% of those who received placebo infusions (hazard ratio, 0.457; P = .01). The teplizumab group had a greater average C-peptide area under the curve compared with placebo, reflecting improved beta-cell function (1.96 vs. 1.68 pmol/mL; P = .006).
C-peptide levels declined over time in the placebo group but stabilized in those receiving teplizumab (P = .0015).
“The mid-range time from randomization to stage 3 type 1 diabetes diagnosis was 50 months for the patients who received Tzield and 25 months for those who received a placebo. This represents a statistically significant delay in the development of stage 3 type 1 diabetes,” according to the FDA statement.
The most common side effects of Tzield include lymphopenia (73% teplizumab vs. 6% placebo), rash (36% vs. 0%), leukopenia (221% vs. 0%), and headache (11% vs. 6%). Label warnings and precautions include monitoring for cytokine release syndrome, risk for serious infections, and avoidance of live, inactivated, and mRNA vaccines.
This approval is likely to accelerate discussion about universal autoantibody screening. Currently, most individuals identified as having preclinical type 1 diabetes are first-degree relatives of people with type 1 diabetes identified through the federally funded TrialNet program. In December 2020, the type 1 diabetes research and advocacy organization JDRF began offering a $55 home blood test to screen for the antibodies, and other screening programs have been launched in the United States and Europe.
Previous studies have examined cost-effectiveness of universal screening in children and the optimal ages that such screening should take place.
In October, Provention Bio announced a co-promotion agreement with Sanofi for the U.S. launch of Tzield for delay in onset of clinical T1D in at-risk individuals. Provention Bio offers financial assistance options (e.g., copay assistance) to eligible patients for out-of-pocket costs.
A version of this article first appeared on Medscape.com.
New and Improved Devices Add More Therapeutic Options for Treatment of Migraine
Since the mid-2010s, the US Food and Drug Administration (FDA) has approved or cleared no fewer than 10 migraine treatments in the form of orals, injectables, nasal sprays, and devices. The medical achievements of the last decade in the field of migraine have been nothing less than stunning for physicians and their patients, whether they relied on off-label medications or those sanctioned by the FDA to treat patients living with migraine.
That said, the newer orals and injectables cannot help everyone living with migraine. The small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and the monoclonal antibodies that target the CGRP ligand or receptor, while well received by patients and physicians alike, have drawbacks for some patients, including lack of efficacy, slow response rate, and adverse events that prevent some patients from taking them. The gepants, which are oral medications—as opposed to the CGRP monoclonal antibody injectables—can occasionally cause enough nausea, drowsiness, and constipation for patients to choose to discontinue their use.
Certain patients have other reasons to shun orals and injectables. Some cannot swallow pills while others fear or do not tolerate injections. Insurance companies limit the quantity of acute care medications, so some patients cannot treat every migraine attack. Then there are those who have failed so many therapies in the past that they will not try the latest one. Consequently, some lie in bed, vomiting until the pain is gone, and some take too many over-the-counter or migraine-specific products, which make migraine symptoms worse if they develop medication overuse headache. And lastly, there are patients who have never walked through a physician’s door to secure a migraine diagnosis and get appropriate treatment.
Non interventional medical devices cleared by the FDA now allow physicians to offer relief to patients with migraine. They work either through various types of electrical neuromodulation to nerves outside the brain or they apply magnetic stimulation to the back of the brain itself to reach pain-associated pathways. A 2019 report on pain management from the US Department of Health and Human Services noted that some randomized control trials (RCTs) and other studies “have demonstrated that noninvasive vagal nerve stimulation can be effective in ameliorating pain in various types of cluster headaches and migraines.”
At least 3 devices, 1 designed to stimulate both the occipital and trigeminal nerves (eCOT-NS, Relivion, Neurolief Ltd), 1 that stimulates the vagus nerve noninvasively (nVNS, gammaCORE, electroCore), and 1 that stimulates peripheral nerves in the upper arm (remote electrical neuromodulation [REN], Nerivio, Theranica Bio-Electronics Ltd), are FDA cleared to treat episodic and chronic migraine. nVNS is also cleared to treat migraine, episodic cluster headache acutely, and chronic cluster acutely in connection with medication.
Real-world studies on all migraine treatments, especially the devices, are flooding PubMed. As for a physician’s observation, we will get to that shortly.
The Devices
Nerivio
Theranica Bio-Electronics Ltd makes a REN called Nerivio, which was FDA cleared in January 2021 to treat episodic migraine acutely in adults and adolescents. Studies have shown its effectiveness for chronic migraine patients who are treated acutely, and it has also helped patients with menstrual migraine. The patient wears the device on the upper arm. Sensory fibers, once stimulated in the arm, send an impulse to the brainstem to affect the serotonin- and norepinephrine-modulated descending inhibitory pathway to disrupt incoming pain messaging. Theranica has applied to the FDA for clearance to treat patients with chronic migraine, as well as for prevention.
Relivion
Neurolief Ltd created the external combined occipital and trigeminal nerve stimulation device (eCOT-NS), which stimulates both the occipital and trigeminal nerves. It has multiple output electrodes, which are placed on the forehead to stimulate the trigeminal supraorbital and supratrochlear nerve branches bilaterally, and over the occipital nerves in the back of the head. It is worn like a tiara as it must be in good contact with the forehead and the back of the head simultaneously. It is FDA cleared to treat acute migraine.
gammaCORE
gammaCORE is a nVNS device that is FDA cleared for acute and preventive treatment of migraine in adolescents and adults, and acute and preventive treatment of episodic cluster headache in adults. It is also cleared to treat chronic cluster headache acutely along with medication. The patient applies gel to the device’s 2 electrical contacts and then locates the vagus nerve on the side of the neck and applies the electrodes to the area that will be treated. Patients can adjust the stimulation’s intensity so that they can barely feel the stimulation; it has not been reported to be painful. nVNS is also an FDA cleared treatment for paroxysmal hemicrania and hemicrania continua.
SAVI Dual
The s-TMS (SAVI Dual, formerly called the Spring TMS and the sTMS mini), made by eNeura, is a single-pulse, transcranial magnetic stimulation applied to the back of the head to stimulate the occipital lobes in the brain. It was FDA cleared for acute and preventive care of migraine in adolescents over 12 years and for adults in February 2019. The patient holds a handheld magnetic device against their occiput, and when the tool is discharged, a brief magnetic pulse interrupts the pattern of neuronal firing (probably cortical spreading depression) that can trigger migraine and the visual aura associated with migraine in one-third of patients.
Cefaly
The e-TNS (Cefaly) works by external trigeminal nerve stimulation of the supraorbital and trochlear nerves bilaterally in the forehead. It gradually and automatically increases in intensity and can be controlled by the patient. It is FDA cleared for acute and preventive treatment of migraine, and, unlike the other devices, it is sold over the counter without a prescription. According to the company website, there are 3 devices: 1 is for acute treatment, 1 is for preventive treatment, and 1 device has 2 settings for both acute and preventive treatment.
The Studies
While most of the published studies on devices are company-sponsored, these device makers have underwritten numerous, sometimes very well-designed, studies on their products. A review by VanderPluym et al described those studies and their various risks of bias.
There are at least 10 studies on REN published so far. These include 2 randomized, sham-controlled trials looking at pain freedom and pain relief at 2 hours after stimulation begins. Another study detailed treatment reports from many patients in which 66.5% experienced pain relief at 2 hours post treatment initiation in half of their treatments. A subgroup of 16% of those patients were prescribed REN by their primary care physicians. Of that group, 77.8% experienced pain relief in half their treatments. That figure was very close to another study that found that 23 of 31 (74.2%) of the study patients treated virtually by non headache providers found relief in 50% of their headaches. REN comes with an education and behavioral medicine app that is used during treatment. A study done by the company shows that when a patient uses the relaxation app along with the standard stimulation, they do considerably better than with stimulation alone.
The eCOT-NS has also been tested in an RCT. At 2 hours, the responder rate was twice as high as in the sham group (66.7% vs 32%). Overall headache relief at 2 hours was higher in the responder group (76% vs 31.6%). In a study collecting real-world data on the efficacy of eCOT-NS in the preventive treatment of migraine (abstract data were presented at the American Headache Society meeting in June 2022), there was a 65.3% reduction in monthly migraine days (MMD) from baseline through 6 months. Treatment reduced MMD by 10.0 (from 15.3 to 5.3—a 76.8% reduction), and reduced acute medication use days (12.5 at baseline to 2.9) at 6 months.
Users of nVNS discussed their experiences with the device, which is the size of a large bar of soap, in a patient registry. They reported 192 attacks, with a mean pain score starting at 2.7 and dropping to 1.3 after 30 minutes. The pain levels of 70% of the attacks dropped to either mild or nonexistent. In a multicenter study on nNVS, 48 patients and 44 sham patients with episodic and chronic cluster headache showed no significant difference in the primary endpoint of pain freedom at 15 minutes between the nVNS and sham. There was also no difference in the chronic cluster headache group. But the episodic cluster subgroup showed a difference; nVNS was superior to sham, 48% to 6% (P
The e-TNS device is cleared for treating adults with migraine, acutely and preventively. It received initial clearance in 2017; in 2020, Cefaly Technology received clearance from the FDA to sell its products over the counter. The device, which resembles a large diamond that affixes to the forehead, has received differing reviews between various patient reports (found online at major retailer sites) and study results. In a blinded, intent-to-treat study involving 538 patients, 25.5% of the verum group reported they were pain-free at 2 hours; 18.3% in the sham group reported the same. Additionally, 56.4% of the subjects in the verum group reported they were free of the most bothersome migraine symptoms, as opposed to 42.3% of the sham group.
Adverse Events
The adverse events observed with these devices were, overall, relatively mild, and disappeared once the device was shut off. A few nVNS users said they experienced discomfort at the application site. With REN, 59 of 12,368 patients reported device-related issues; the vast majority were considered mild and consisted mostly of a sensation of warmth under the device. Of the 259 e-TNS users, 8.5% reported minor and reversible occurrences, such as treatment-related discomfort, paresthesia, and burning.
Patients in the Clinic
A few observations from the clinic regarding these devices:
Some devices are easier to use than others. I know this, because at a recent demonstration session in a course for physicians on headache treatment, I agreed to be the person on whom the device was demonstrated. The physician applying the device had difficulty aligning the device’s sensors with the appropriate nerves. Making sure your patients use these devices correctly is essential, and you or your staff should demonstrate their use to the patient. No doubt, this could be time-consuming in some cases, and patients who are reading the device’s instructions while in pain will likely get frustrated if they cannot get the device to work.
Some patients who have failed every medication class can occasionally find partial relief with these devices. One longtime patient of mine came to me severely disabled from chronic migraine and medication overuse headache but was somewhat better with 2 preventive medications. Triptans worked acutely, but she developed nearly every side effect imaginable. I was able to reverse her medication overuse headache, but the gepants, although they worked somewhat, took too long to take effect. We agreed the next step would be to use REN for each migraine attack, combined with acute care medication if necessary. (She uses REN alone for a milder headache and adds a gepant with naproxen if necessary.) She has found using the relaxation module on the REN app increases her chances of eliminating the migraine. She is not pain free all the time, but she appreciates the pain-free intervals.
One chronic cluster patient has relied on subcutaneous sumatriptan and breathing 100% oxygen at 12 liters per minute through a mask over his nose and mouth for acute relief from his headaches. His headache pain can climb from a 3 to a 10 in a matter of minutes. It starts behind and a bit above the right eye where he feels a tremendous pressure building up. He says that at times it feels like a screwdriver has been thrust into his eye and is being turned. Along with the pain, the eye becomes red, the pupil constricts, and the eyelid droops. He also has dripping from the right nostril, which stuffs up when the pain abates. The pain lasts for 1 to 2 hours, then returns 3 to 5 times a day for 5 days a week, on average. The pain never goes away for more than 3 weeks in a year’s time, hence the reason for his chronic cluster headache diagnosis. He is now using nVNS as soon as he feels the pain coming on. If the device does not provide sufficient relief, he uses oxygen or takes the sumatriptan injection.
Some patients who get cluster headaches think of suicide if the pain cannot be stopped; but in my experience, most can become pain free, or at least realize some partial relief from a variety of treatments (sometimes given at the same time).
Doctors often do not think of devices as options, and some doctors think devices do not work even though they have no experience with using them. Devices can give good relief on their own, and when a severe headache needs stronger treatment, medications added to a device usually work better than either treatment alone.
Since the mid-2010s, the US Food and Drug Administration (FDA) has approved or cleared no fewer than 10 migraine treatments in the form of orals, injectables, nasal sprays, and devices. The medical achievements of the last decade in the field of migraine have been nothing less than stunning for physicians and their patients, whether they relied on off-label medications or those sanctioned by the FDA to treat patients living with migraine.
That said, the newer orals and injectables cannot help everyone living with migraine. The small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and the monoclonal antibodies that target the CGRP ligand or receptor, while well received by patients and physicians alike, have drawbacks for some patients, including lack of efficacy, slow response rate, and adverse events that prevent some patients from taking them. The gepants, which are oral medications—as opposed to the CGRP monoclonal antibody injectables—can occasionally cause enough nausea, drowsiness, and constipation for patients to choose to discontinue their use.
Certain patients have other reasons to shun orals and injectables. Some cannot swallow pills while others fear or do not tolerate injections. Insurance companies limit the quantity of acute care medications, so some patients cannot treat every migraine attack. Then there are those who have failed so many therapies in the past that they will not try the latest one. Consequently, some lie in bed, vomiting until the pain is gone, and some take too many over-the-counter or migraine-specific products, which make migraine symptoms worse if they develop medication overuse headache. And lastly, there are patients who have never walked through a physician’s door to secure a migraine diagnosis and get appropriate treatment.
Non interventional medical devices cleared by the FDA now allow physicians to offer relief to patients with migraine. They work either through various types of electrical neuromodulation to nerves outside the brain or they apply magnetic stimulation to the back of the brain itself to reach pain-associated pathways. A 2019 report on pain management from the US Department of Health and Human Services noted that some randomized control trials (RCTs) and other studies “have demonstrated that noninvasive vagal nerve stimulation can be effective in ameliorating pain in various types of cluster headaches and migraines.”
At least 3 devices, 1 designed to stimulate both the occipital and trigeminal nerves (eCOT-NS, Relivion, Neurolief Ltd), 1 that stimulates the vagus nerve noninvasively (nVNS, gammaCORE, electroCore), and 1 that stimulates peripheral nerves in the upper arm (remote electrical neuromodulation [REN], Nerivio, Theranica Bio-Electronics Ltd), are FDA cleared to treat episodic and chronic migraine. nVNS is also cleared to treat migraine, episodic cluster headache acutely, and chronic cluster acutely in connection with medication.
Real-world studies on all migraine treatments, especially the devices, are flooding PubMed. As for a physician’s observation, we will get to that shortly.
The Devices
Nerivio
Theranica Bio-Electronics Ltd makes a REN called Nerivio, which was FDA cleared in January 2021 to treat episodic migraine acutely in adults and adolescents. Studies have shown its effectiveness for chronic migraine patients who are treated acutely, and it has also helped patients with menstrual migraine. The patient wears the device on the upper arm. Sensory fibers, once stimulated in the arm, send an impulse to the brainstem to affect the serotonin- and norepinephrine-modulated descending inhibitory pathway to disrupt incoming pain messaging. Theranica has applied to the FDA for clearance to treat patients with chronic migraine, as well as for prevention.
Relivion
Neurolief Ltd created the external combined occipital and trigeminal nerve stimulation device (eCOT-NS), which stimulates both the occipital and trigeminal nerves. It has multiple output electrodes, which are placed on the forehead to stimulate the trigeminal supraorbital and supratrochlear nerve branches bilaterally, and over the occipital nerves in the back of the head. It is worn like a tiara as it must be in good contact with the forehead and the back of the head simultaneously. It is FDA cleared to treat acute migraine.
gammaCORE
gammaCORE is a nVNS device that is FDA cleared for acute and preventive treatment of migraine in adolescents and adults, and acute and preventive treatment of episodic cluster headache in adults. It is also cleared to treat chronic cluster headache acutely along with medication. The patient applies gel to the device’s 2 electrical contacts and then locates the vagus nerve on the side of the neck and applies the electrodes to the area that will be treated. Patients can adjust the stimulation’s intensity so that they can barely feel the stimulation; it has not been reported to be painful. nVNS is also an FDA cleared treatment for paroxysmal hemicrania and hemicrania continua.
SAVI Dual
The s-TMS (SAVI Dual, formerly called the Spring TMS and the sTMS mini), made by eNeura, is a single-pulse, transcranial magnetic stimulation applied to the back of the head to stimulate the occipital lobes in the brain. It was FDA cleared for acute and preventive care of migraine in adolescents over 12 years and for adults in February 2019. The patient holds a handheld magnetic device against their occiput, and when the tool is discharged, a brief magnetic pulse interrupts the pattern of neuronal firing (probably cortical spreading depression) that can trigger migraine and the visual aura associated with migraine in one-third of patients.
Cefaly
The e-TNS (Cefaly) works by external trigeminal nerve stimulation of the supraorbital and trochlear nerves bilaterally in the forehead. It gradually and automatically increases in intensity and can be controlled by the patient. It is FDA cleared for acute and preventive treatment of migraine, and, unlike the other devices, it is sold over the counter without a prescription. According to the company website, there are 3 devices: 1 is for acute treatment, 1 is for preventive treatment, and 1 device has 2 settings for both acute and preventive treatment.
The Studies
While most of the published studies on devices are company-sponsored, these device makers have underwritten numerous, sometimes very well-designed, studies on their products. A review by VanderPluym et al described those studies and their various risks of bias.
There are at least 10 studies on REN published so far. These include 2 randomized, sham-controlled trials looking at pain freedom and pain relief at 2 hours after stimulation begins. Another study detailed treatment reports from many patients in which 66.5% experienced pain relief at 2 hours post treatment initiation in half of their treatments. A subgroup of 16% of those patients were prescribed REN by their primary care physicians. Of that group, 77.8% experienced pain relief in half their treatments. That figure was very close to another study that found that 23 of 31 (74.2%) of the study patients treated virtually by non headache providers found relief in 50% of their headaches. REN comes with an education and behavioral medicine app that is used during treatment. A study done by the company shows that when a patient uses the relaxation app along with the standard stimulation, they do considerably better than with stimulation alone.
The eCOT-NS has also been tested in an RCT. At 2 hours, the responder rate was twice as high as in the sham group (66.7% vs 32%). Overall headache relief at 2 hours was higher in the responder group (76% vs 31.6%). In a study collecting real-world data on the efficacy of eCOT-NS in the preventive treatment of migraine (abstract data were presented at the American Headache Society meeting in June 2022), there was a 65.3% reduction in monthly migraine days (MMD) from baseline through 6 months. Treatment reduced MMD by 10.0 (from 15.3 to 5.3—a 76.8% reduction), and reduced acute medication use days (12.5 at baseline to 2.9) at 6 months.
Users of nVNS discussed their experiences with the device, which is the size of a large bar of soap, in a patient registry. They reported 192 attacks, with a mean pain score starting at 2.7 and dropping to 1.3 after 30 minutes. The pain levels of 70% of the attacks dropped to either mild or nonexistent. In a multicenter study on nNVS, 48 patients and 44 sham patients with episodic and chronic cluster headache showed no significant difference in the primary endpoint of pain freedom at 15 minutes between the nVNS and sham. There was also no difference in the chronic cluster headache group. But the episodic cluster subgroup showed a difference; nVNS was superior to sham, 48% to 6% (P
The e-TNS device is cleared for treating adults with migraine, acutely and preventively. It received initial clearance in 2017; in 2020, Cefaly Technology received clearance from the FDA to sell its products over the counter. The device, which resembles a large diamond that affixes to the forehead, has received differing reviews between various patient reports (found online at major retailer sites) and study results. In a blinded, intent-to-treat study involving 538 patients, 25.5% of the verum group reported they were pain-free at 2 hours; 18.3% in the sham group reported the same. Additionally, 56.4% of the subjects in the verum group reported they were free of the most bothersome migraine symptoms, as opposed to 42.3% of the sham group.
Adverse Events
The adverse events observed with these devices were, overall, relatively mild, and disappeared once the device was shut off. A few nVNS users said they experienced discomfort at the application site. With REN, 59 of 12,368 patients reported device-related issues; the vast majority were considered mild and consisted mostly of a sensation of warmth under the device. Of the 259 e-TNS users, 8.5% reported minor and reversible occurrences, such as treatment-related discomfort, paresthesia, and burning.
Patients in the Clinic
A few observations from the clinic regarding these devices:
Some devices are easier to use than others. I know this, because at a recent demonstration session in a course for physicians on headache treatment, I agreed to be the person on whom the device was demonstrated. The physician applying the device had difficulty aligning the device’s sensors with the appropriate nerves. Making sure your patients use these devices correctly is essential, and you or your staff should demonstrate their use to the patient. No doubt, this could be time-consuming in some cases, and patients who are reading the device’s instructions while in pain will likely get frustrated if they cannot get the device to work.
Some patients who have failed every medication class can occasionally find partial relief with these devices. One longtime patient of mine came to me severely disabled from chronic migraine and medication overuse headache but was somewhat better with 2 preventive medications. Triptans worked acutely, but she developed nearly every side effect imaginable. I was able to reverse her medication overuse headache, but the gepants, although they worked somewhat, took too long to take effect. We agreed the next step would be to use REN for each migraine attack, combined with acute care medication if necessary. (She uses REN alone for a milder headache and adds a gepant with naproxen if necessary.) She has found using the relaxation module on the REN app increases her chances of eliminating the migraine. She is not pain free all the time, but she appreciates the pain-free intervals.
One chronic cluster patient has relied on subcutaneous sumatriptan and breathing 100% oxygen at 12 liters per minute through a mask over his nose and mouth for acute relief from his headaches. His headache pain can climb from a 3 to a 10 in a matter of minutes. It starts behind and a bit above the right eye where he feels a tremendous pressure building up. He says that at times it feels like a screwdriver has been thrust into his eye and is being turned. Along with the pain, the eye becomes red, the pupil constricts, and the eyelid droops. He also has dripping from the right nostril, which stuffs up when the pain abates. The pain lasts for 1 to 2 hours, then returns 3 to 5 times a day for 5 days a week, on average. The pain never goes away for more than 3 weeks in a year’s time, hence the reason for his chronic cluster headache diagnosis. He is now using nVNS as soon as he feels the pain coming on. If the device does not provide sufficient relief, he uses oxygen or takes the sumatriptan injection.
Some patients who get cluster headaches think of suicide if the pain cannot be stopped; but in my experience, most can become pain free, or at least realize some partial relief from a variety of treatments (sometimes given at the same time).
Doctors often do not think of devices as options, and some doctors think devices do not work even though they have no experience with using them. Devices can give good relief on their own, and when a severe headache needs stronger treatment, medications added to a device usually work better than either treatment alone.
Since the mid-2010s, the US Food and Drug Administration (FDA) has approved or cleared no fewer than 10 migraine treatments in the form of orals, injectables, nasal sprays, and devices. The medical achievements of the last decade in the field of migraine have been nothing less than stunning for physicians and their patients, whether they relied on off-label medications or those sanctioned by the FDA to treat patients living with migraine.
That said, the newer orals and injectables cannot help everyone living with migraine. The small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) and the monoclonal antibodies that target the CGRP ligand or receptor, while well received by patients and physicians alike, have drawbacks for some patients, including lack of efficacy, slow response rate, and adverse events that prevent some patients from taking them. The gepants, which are oral medications—as opposed to the CGRP monoclonal antibody injectables—can occasionally cause enough nausea, drowsiness, and constipation for patients to choose to discontinue their use.
Certain patients have other reasons to shun orals and injectables. Some cannot swallow pills while others fear or do not tolerate injections. Insurance companies limit the quantity of acute care medications, so some patients cannot treat every migraine attack. Then there are those who have failed so many therapies in the past that they will not try the latest one. Consequently, some lie in bed, vomiting until the pain is gone, and some take too many over-the-counter or migraine-specific products, which make migraine symptoms worse if they develop medication overuse headache. And lastly, there are patients who have never walked through a physician’s door to secure a migraine diagnosis and get appropriate treatment.
Non interventional medical devices cleared by the FDA now allow physicians to offer relief to patients with migraine. They work either through various types of electrical neuromodulation to nerves outside the brain or they apply magnetic stimulation to the back of the brain itself to reach pain-associated pathways. A 2019 report on pain management from the US Department of Health and Human Services noted that some randomized control trials (RCTs) and other studies “have demonstrated that noninvasive vagal nerve stimulation can be effective in ameliorating pain in various types of cluster headaches and migraines.”
At least 3 devices, 1 designed to stimulate both the occipital and trigeminal nerves (eCOT-NS, Relivion, Neurolief Ltd), 1 that stimulates the vagus nerve noninvasively (nVNS, gammaCORE, electroCore), and 1 that stimulates peripheral nerves in the upper arm (remote electrical neuromodulation [REN], Nerivio, Theranica Bio-Electronics Ltd), are FDA cleared to treat episodic and chronic migraine. nVNS is also cleared to treat migraine, episodic cluster headache acutely, and chronic cluster acutely in connection with medication.
Real-world studies on all migraine treatments, especially the devices, are flooding PubMed. As for a physician’s observation, we will get to that shortly.
The Devices
Nerivio
Theranica Bio-Electronics Ltd makes a REN called Nerivio, which was FDA cleared in January 2021 to treat episodic migraine acutely in adults and adolescents. Studies have shown its effectiveness for chronic migraine patients who are treated acutely, and it has also helped patients with menstrual migraine. The patient wears the device on the upper arm. Sensory fibers, once stimulated in the arm, send an impulse to the brainstem to affect the serotonin- and norepinephrine-modulated descending inhibitory pathway to disrupt incoming pain messaging. Theranica has applied to the FDA for clearance to treat patients with chronic migraine, as well as for prevention.
Relivion
Neurolief Ltd created the external combined occipital and trigeminal nerve stimulation device (eCOT-NS), which stimulates both the occipital and trigeminal nerves. It has multiple output electrodes, which are placed on the forehead to stimulate the trigeminal supraorbital and supratrochlear nerve branches bilaterally, and over the occipital nerves in the back of the head. It is worn like a tiara as it must be in good contact with the forehead and the back of the head simultaneously. It is FDA cleared to treat acute migraine.
gammaCORE
gammaCORE is a nVNS device that is FDA cleared for acute and preventive treatment of migraine in adolescents and adults, and acute and preventive treatment of episodic cluster headache in adults. It is also cleared to treat chronic cluster headache acutely along with medication. The patient applies gel to the device’s 2 electrical contacts and then locates the vagus nerve on the side of the neck and applies the electrodes to the area that will be treated. Patients can adjust the stimulation’s intensity so that they can barely feel the stimulation; it has not been reported to be painful. nVNS is also an FDA cleared treatment for paroxysmal hemicrania and hemicrania continua.
SAVI Dual
The s-TMS (SAVI Dual, formerly called the Spring TMS and the sTMS mini), made by eNeura, is a single-pulse, transcranial magnetic stimulation applied to the back of the head to stimulate the occipital lobes in the brain. It was FDA cleared for acute and preventive care of migraine in adolescents over 12 years and for adults in February 2019. The patient holds a handheld magnetic device against their occiput, and when the tool is discharged, a brief magnetic pulse interrupts the pattern of neuronal firing (probably cortical spreading depression) that can trigger migraine and the visual aura associated with migraine in one-third of patients.
Cefaly
The e-TNS (Cefaly) works by external trigeminal nerve stimulation of the supraorbital and trochlear nerves bilaterally in the forehead. It gradually and automatically increases in intensity and can be controlled by the patient. It is FDA cleared for acute and preventive treatment of migraine, and, unlike the other devices, it is sold over the counter without a prescription. According to the company website, there are 3 devices: 1 is for acute treatment, 1 is for preventive treatment, and 1 device has 2 settings for both acute and preventive treatment.
The Studies
While most of the published studies on devices are company-sponsored, these device makers have underwritten numerous, sometimes very well-designed, studies on their products. A review by VanderPluym et al described those studies and their various risks of bias.
There are at least 10 studies on REN published so far. These include 2 randomized, sham-controlled trials looking at pain freedom and pain relief at 2 hours after stimulation begins. Another study detailed treatment reports from many patients in which 66.5% experienced pain relief at 2 hours post treatment initiation in half of their treatments. A subgroup of 16% of those patients were prescribed REN by their primary care physicians. Of that group, 77.8% experienced pain relief in half their treatments. That figure was very close to another study that found that 23 of 31 (74.2%) of the study patients treated virtually by non headache providers found relief in 50% of their headaches. REN comes with an education and behavioral medicine app that is used during treatment. A study done by the company shows that when a patient uses the relaxation app along with the standard stimulation, they do considerably better than with stimulation alone.
The eCOT-NS has also been tested in an RCT. At 2 hours, the responder rate was twice as high as in the sham group (66.7% vs 32%). Overall headache relief at 2 hours was higher in the responder group (76% vs 31.6%). In a study collecting real-world data on the efficacy of eCOT-NS in the preventive treatment of migraine (abstract data were presented at the American Headache Society meeting in June 2022), there was a 65.3% reduction in monthly migraine days (MMD) from baseline through 6 months. Treatment reduced MMD by 10.0 (from 15.3 to 5.3—a 76.8% reduction), and reduced acute medication use days (12.5 at baseline to 2.9) at 6 months.
Users of nVNS discussed their experiences with the device, which is the size of a large bar of soap, in a patient registry. They reported 192 attacks, with a mean pain score starting at 2.7 and dropping to 1.3 after 30 minutes. The pain levels of 70% of the attacks dropped to either mild or nonexistent. In a multicenter study on nNVS, 48 patients and 44 sham patients with episodic and chronic cluster headache showed no significant difference in the primary endpoint of pain freedom at 15 minutes between the nVNS and sham. There was also no difference in the chronic cluster headache group. But the episodic cluster subgroup showed a difference; nVNS was superior to sham, 48% to 6% (P
The e-TNS device is cleared for treating adults with migraine, acutely and preventively. It received initial clearance in 2017; in 2020, Cefaly Technology received clearance from the FDA to sell its products over the counter. The device, which resembles a large diamond that affixes to the forehead, has received differing reviews between various patient reports (found online at major retailer sites) and study results. In a blinded, intent-to-treat study involving 538 patients, 25.5% of the verum group reported they were pain-free at 2 hours; 18.3% in the sham group reported the same. Additionally, 56.4% of the subjects in the verum group reported they were free of the most bothersome migraine symptoms, as opposed to 42.3% of the sham group.
Adverse Events
The adverse events observed with these devices were, overall, relatively mild, and disappeared once the device was shut off. A few nVNS users said they experienced discomfort at the application site. With REN, 59 of 12,368 patients reported device-related issues; the vast majority were considered mild and consisted mostly of a sensation of warmth under the device. Of the 259 e-TNS users, 8.5% reported minor and reversible occurrences, such as treatment-related discomfort, paresthesia, and burning.
Patients in the Clinic
A few observations from the clinic regarding these devices:
Some devices are easier to use than others. I know this, because at a recent demonstration session in a course for physicians on headache treatment, I agreed to be the person on whom the device was demonstrated. The physician applying the device had difficulty aligning the device’s sensors with the appropriate nerves. Making sure your patients use these devices correctly is essential, and you or your staff should demonstrate their use to the patient. No doubt, this could be time-consuming in some cases, and patients who are reading the device’s instructions while in pain will likely get frustrated if they cannot get the device to work.
Some patients who have failed every medication class can occasionally find partial relief with these devices. One longtime patient of mine came to me severely disabled from chronic migraine and medication overuse headache but was somewhat better with 2 preventive medications. Triptans worked acutely, but she developed nearly every side effect imaginable. I was able to reverse her medication overuse headache, but the gepants, although they worked somewhat, took too long to take effect. We agreed the next step would be to use REN for each migraine attack, combined with acute care medication if necessary. (She uses REN alone for a milder headache and adds a gepant with naproxen if necessary.) She has found using the relaxation module on the REN app increases her chances of eliminating the migraine. She is not pain free all the time, but she appreciates the pain-free intervals.
One chronic cluster patient has relied on subcutaneous sumatriptan and breathing 100% oxygen at 12 liters per minute through a mask over his nose and mouth for acute relief from his headaches. His headache pain can climb from a 3 to a 10 in a matter of minutes. It starts behind and a bit above the right eye where he feels a tremendous pressure building up. He says that at times it feels like a screwdriver has been thrust into his eye and is being turned. Along with the pain, the eye becomes red, the pupil constricts, and the eyelid droops. He also has dripping from the right nostril, which stuffs up when the pain abates. The pain lasts for 1 to 2 hours, then returns 3 to 5 times a day for 5 days a week, on average. The pain never goes away for more than 3 weeks in a year’s time, hence the reason for his chronic cluster headache diagnosis. He is now using nVNS as soon as he feels the pain coming on. If the device does not provide sufficient relief, he uses oxygen or takes the sumatriptan injection.
Some patients who get cluster headaches think of suicide if the pain cannot be stopped; but in my experience, most can become pain free, or at least realize some partial relief from a variety of treatments (sometimes given at the same time).
Doctors often do not think of devices as options, and some doctors think devices do not work even though they have no experience with using them. Devices can give good relief on their own, and when a severe headache needs stronger treatment, medications added to a device usually work better than either treatment alone.
HIV: Greater parental involvement needed with young men who have sex with men
“Take it from me, parents just don’t understand.”
Fresh Prince and D.J. Jazzy Jeff penned this lyric roughly 35 years ago, and coincidentally the HIV/AIDS epidemic has also been with us just as long. But the connection between the two may be highly relevant – that is, if you consider how infrequently parents appear (or have the proper tools) to engage with their gay or bisexual sons to prevent and curb HIV infections.
Currently, YMSM between the ages of 13 and 24 are among the most affected by the ongoing HIV epidemic, with CDC estimates suggesting that, in 2020, this group alone represented about 35% of new diagnoses. At the same time, about half of these HIV infections go undiagnosed. Recent data also suggest that care linkage in this group is similar to adults, but only a third of YMSM start antiretroviral therapy and are retained in care, leading to viral suppression rates as low as 12%.
With a goal to change these discouraging numbers, researchers from George Washington University, Washington, and other institutions conducted a randomized controlled pilot study targeting parents of YMSM to improve both the frequency and quality of communication around sexual health and HIV risk, prevention, and testing.
The findings, which were published online in the journal AIDS and Behavior, highlight the observation that parents could be an essential resource for combating the HIV epidemic, but they’re a resource that’s often underutilized. In fact, after participating in an online offering – PATHS (Parents and Adolescents Talking about Healthy Sexuality) – parents reported significantly greater engagement with their sons, especially around discussions focusing on HIV information and condom use.
“From what we know from the research, parents are uncomfortable talking about sex; they’re not great at talking about it. But when they do and do it effectively, those kids seem to have better health outcomes,” lead author David Huebner, PhD, MPH, associate professor of prevention and community health at George Washington University, said in an interview.
“The goal was to get parents to deliver more messages and engage in more behaviors with their sons that we think are likely to help their sons stay healthy,” he said.
For the pilot study, Huebner and his team recruited 61 parents (95% of whom were mothers) with predominantly high school-aged cisgender sons (median, 16.7-17 years) who had come out as gay or bisexual at least a month prior, whose HIV status was negative or unknown, and who were living at home.
The interventions were strictly parent focused, Dr. Huebner said, noting that the only interaction with the kids involved independent surveys at the start and end of the study that explored parental behavior and engagement.
For the study, parental participants were stratified by son’s age (13-17 or 18-22 years) and then randomly assigned to participate in a web-accessible PATHS intervention (intervention group) or view a 35-minute, documentary-style film that encouraged acceptance of lesbian, gay, or bisexual children (control group),
Parents assigned to the intervention group were asked to engage in their own time with six modules that explored the importance of communication, HIV information, using and acquiring condoms, HIV testing, and as follow-up, a “to-do” list encouraging selection of how they would follow up with their sons about the content. They were also offered the option to participate in supplemental modules on pre-exposure prophylaxis (PrEP), anal intercourse, and what to do if a child tested positive for HIV.
“The intervention ... showed strong evidence of being effective at changing the parent behaviors that we hoped to change,” Dr. Huebner explained.
“We got independent reports from parents and kids that showed the same thing: parents were more likely to communicate with their sons about HIV in the 3 months after the intervention and were more likely to help their sons get access to condoms,” he said.
Both of these findings were significant, with parents in the experimental group being almost 10 times more likely to share HIV information with their sons (odds ratio, 9.50; 95% confidence interval, 1.02-39.99; P < .05) and five times more likely to teach proper condom use (OR, 5.04; 95% CI 1.56-12.46; P < .05), compared with parents receiving the placebo.
“It’s very promising that the initial signals from their intervention do show that parents facilitating the acquisition of information for young men who have sex with men really works,” said Dalmacio Dennis Flores, PhD, ACRN, an assistant professor of nursing in family and community health at the University of Pennsylvania, Philadelphia. He was not directly involved in the study.
“On the outcomes that matter for us, such as HIV prevention or getting tested, they were able to document that parents receiving guidance on how to have these conversations does result in youth outcomes – something that has been lacking in the literature specifically for this population up until today,” Dr. Flores told this news organization.
Overall, parents engaging in the PATHS intervention showed improvements in skills, attitudes, and behavioral intention toward engagement with their sons, including assisting with HIV testing. However, what about parental involvement in these types of dialogues with children who have not yet come out to their parents?
Dr. Flores said that, although Dr. Huebner’s work is pivotal for families where the child’s sexual orientation is known to parents, there is value in inclusive sex communication for all youth, regardless of how they identify (that is, out of the closet, closeted, straight, or those who are questioning their identity), especially since younger generations of LGBTQ youth are coming out at earlier ages, compared with previous generations.
It’s not just parents. Clinicians also have critical roles to play in helping bridge the sex-talk communication gaps between parents and adolescents and young adult children.
“In my work, I’ve found that more clinicians are willing to broach this within the discussion with dyads, with parents and adolescents in the room,” said Dr. Flores.
And he added: “If clinicians signal that there’s no such thing as too early to have these conversations or that issues such as consent, safety, and sexting are all okay to talk about because these are the current realities of young people, then parents can feel that they’re empowered to broach or sustain these conversations.”
Importantly, Dr. Huebner and associates are currently recruiting larger numbers of families for a new, yearlong trial that will not only examine parental behavior changes but also whether these changes translate into improvements in their child’s sexual health and/or competency. Interested families can learn more about the study and sign up to receive updates at www.parentwithlove.org.
Dr. Huebner and Dr. Flores reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“Take it from me, parents just don’t understand.”
Fresh Prince and D.J. Jazzy Jeff penned this lyric roughly 35 years ago, and coincidentally the HIV/AIDS epidemic has also been with us just as long. But the connection between the two may be highly relevant – that is, if you consider how infrequently parents appear (or have the proper tools) to engage with their gay or bisexual sons to prevent and curb HIV infections.
Currently, YMSM between the ages of 13 and 24 are among the most affected by the ongoing HIV epidemic, with CDC estimates suggesting that, in 2020, this group alone represented about 35% of new diagnoses. At the same time, about half of these HIV infections go undiagnosed. Recent data also suggest that care linkage in this group is similar to adults, but only a third of YMSM start antiretroviral therapy and are retained in care, leading to viral suppression rates as low as 12%.
With a goal to change these discouraging numbers, researchers from George Washington University, Washington, and other institutions conducted a randomized controlled pilot study targeting parents of YMSM to improve both the frequency and quality of communication around sexual health and HIV risk, prevention, and testing.
The findings, which were published online in the journal AIDS and Behavior, highlight the observation that parents could be an essential resource for combating the HIV epidemic, but they’re a resource that’s often underutilized. In fact, after participating in an online offering – PATHS (Parents and Adolescents Talking about Healthy Sexuality) – parents reported significantly greater engagement with their sons, especially around discussions focusing on HIV information and condom use.
“From what we know from the research, parents are uncomfortable talking about sex; they’re not great at talking about it. But when they do and do it effectively, those kids seem to have better health outcomes,” lead author David Huebner, PhD, MPH, associate professor of prevention and community health at George Washington University, said in an interview.
“The goal was to get parents to deliver more messages and engage in more behaviors with their sons that we think are likely to help their sons stay healthy,” he said.
For the pilot study, Huebner and his team recruited 61 parents (95% of whom were mothers) with predominantly high school-aged cisgender sons (median, 16.7-17 years) who had come out as gay or bisexual at least a month prior, whose HIV status was negative or unknown, and who were living at home.
The interventions were strictly parent focused, Dr. Huebner said, noting that the only interaction with the kids involved independent surveys at the start and end of the study that explored parental behavior and engagement.
For the study, parental participants were stratified by son’s age (13-17 or 18-22 years) and then randomly assigned to participate in a web-accessible PATHS intervention (intervention group) or view a 35-minute, documentary-style film that encouraged acceptance of lesbian, gay, or bisexual children (control group),
Parents assigned to the intervention group were asked to engage in their own time with six modules that explored the importance of communication, HIV information, using and acquiring condoms, HIV testing, and as follow-up, a “to-do” list encouraging selection of how they would follow up with their sons about the content. They were also offered the option to participate in supplemental modules on pre-exposure prophylaxis (PrEP), anal intercourse, and what to do if a child tested positive for HIV.
“The intervention ... showed strong evidence of being effective at changing the parent behaviors that we hoped to change,” Dr. Huebner explained.
“We got independent reports from parents and kids that showed the same thing: parents were more likely to communicate with their sons about HIV in the 3 months after the intervention and were more likely to help their sons get access to condoms,” he said.
Both of these findings were significant, with parents in the experimental group being almost 10 times more likely to share HIV information with their sons (odds ratio, 9.50; 95% confidence interval, 1.02-39.99; P < .05) and five times more likely to teach proper condom use (OR, 5.04; 95% CI 1.56-12.46; P < .05), compared with parents receiving the placebo.
“It’s very promising that the initial signals from their intervention do show that parents facilitating the acquisition of information for young men who have sex with men really works,” said Dalmacio Dennis Flores, PhD, ACRN, an assistant professor of nursing in family and community health at the University of Pennsylvania, Philadelphia. He was not directly involved in the study.
“On the outcomes that matter for us, such as HIV prevention or getting tested, they were able to document that parents receiving guidance on how to have these conversations does result in youth outcomes – something that has been lacking in the literature specifically for this population up until today,” Dr. Flores told this news organization.
Overall, parents engaging in the PATHS intervention showed improvements in skills, attitudes, and behavioral intention toward engagement with their sons, including assisting with HIV testing. However, what about parental involvement in these types of dialogues with children who have not yet come out to their parents?
Dr. Flores said that, although Dr. Huebner’s work is pivotal for families where the child’s sexual orientation is known to parents, there is value in inclusive sex communication for all youth, regardless of how they identify (that is, out of the closet, closeted, straight, or those who are questioning their identity), especially since younger generations of LGBTQ youth are coming out at earlier ages, compared with previous generations.
It’s not just parents. Clinicians also have critical roles to play in helping bridge the sex-talk communication gaps between parents and adolescents and young adult children.
“In my work, I’ve found that more clinicians are willing to broach this within the discussion with dyads, with parents and adolescents in the room,” said Dr. Flores.
And he added: “If clinicians signal that there’s no such thing as too early to have these conversations or that issues such as consent, safety, and sexting are all okay to talk about because these are the current realities of young people, then parents can feel that they’re empowered to broach or sustain these conversations.”
Importantly, Dr. Huebner and associates are currently recruiting larger numbers of families for a new, yearlong trial that will not only examine parental behavior changes but also whether these changes translate into improvements in their child’s sexual health and/or competency. Interested families can learn more about the study and sign up to receive updates at www.parentwithlove.org.
Dr. Huebner and Dr. Flores reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“Take it from me, parents just don’t understand.”
Fresh Prince and D.J. Jazzy Jeff penned this lyric roughly 35 years ago, and coincidentally the HIV/AIDS epidemic has also been with us just as long. But the connection between the two may be highly relevant – that is, if you consider how infrequently parents appear (or have the proper tools) to engage with their gay or bisexual sons to prevent and curb HIV infections.
Currently, YMSM between the ages of 13 and 24 are among the most affected by the ongoing HIV epidemic, with CDC estimates suggesting that, in 2020, this group alone represented about 35% of new diagnoses. At the same time, about half of these HIV infections go undiagnosed. Recent data also suggest that care linkage in this group is similar to adults, but only a third of YMSM start antiretroviral therapy and are retained in care, leading to viral suppression rates as low as 12%.
With a goal to change these discouraging numbers, researchers from George Washington University, Washington, and other institutions conducted a randomized controlled pilot study targeting parents of YMSM to improve both the frequency and quality of communication around sexual health and HIV risk, prevention, and testing.
The findings, which were published online in the journal AIDS and Behavior, highlight the observation that parents could be an essential resource for combating the HIV epidemic, but they’re a resource that’s often underutilized. In fact, after participating in an online offering – PATHS (Parents and Adolescents Talking about Healthy Sexuality) – parents reported significantly greater engagement with their sons, especially around discussions focusing on HIV information and condom use.
“From what we know from the research, parents are uncomfortable talking about sex; they’re not great at talking about it. But when they do and do it effectively, those kids seem to have better health outcomes,” lead author David Huebner, PhD, MPH, associate professor of prevention and community health at George Washington University, said in an interview.
“The goal was to get parents to deliver more messages and engage in more behaviors with their sons that we think are likely to help their sons stay healthy,” he said.
For the pilot study, Huebner and his team recruited 61 parents (95% of whom were mothers) with predominantly high school-aged cisgender sons (median, 16.7-17 years) who had come out as gay or bisexual at least a month prior, whose HIV status was negative or unknown, and who were living at home.
The interventions were strictly parent focused, Dr. Huebner said, noting that the only interaction with the kids involved independent surveys at the start and end of the study that explored parental behavior and engagement.
For the study, parental participants were stratified by son’s age (13-17 or 18-22 years) and then randomly assigned to participate in a web-accessible PATHS intervention (intervention group) or view a 35-minute, documentary-style film that encouraged acceptance of lesbian, gay, or bisexual children (control group),
Parents assigned to the intervention group were asked to engage in their own time with six modules that explored the importance of communication, HIV information, using and acquiring condoms, HIV testing, and as follow-up, a “to-do” list encouraging selection of how they would follow up with their sons about the content. They were also offered the option to participate in supplemental modules on pre-exposure prophylaxis (PrEP), anal intercourse, and what to do if a child tested positive for HIV.
“The intervention ... showed strong evidence of being effective at changing the parent behaviors that we hoped to change,” Dr. Huebner explained.
“We got independent reports from parents and kids that showed the same thing: parents were more likely to communicate with their sons about HIV in the 3 months after the intervention and were more likely to help their sons get access to condoms,” he said.
Both of these findings were significant, with parents in the experimental group being almost 10 times more likely to share HIV information with their sons (odds ratio, 9.50; 95% confidence interval, 1.02-39.99; P < .05) and five times more likely to teach proper condom use (OR, 5.04; 95% CI 1.56-12.46; P < .05), compared with parents receiving the placebo.
“It’s very promising that the initial signals from their intervention do show that parents facilitating the acquisition of information for young men who have sex with men really works,” said Dalmacio Dennis Flores, PhD, ACRN, an assistant professor of nursing in family and community health at the University of Pennsylvania, Philadelphia. He was not directly involved in the study.
“On the outcomes that matter for us, such as HIV prevention or getting tested, they were able to document that parents receiving guidance on how to have these conversations does result in youth outcomes – something that has been lacking in the literature specifically for this population up until today,” Dr. Flores told this news organization.
Overall, parents engaging in the PATHS intervention showed improvements in skills, attitudes, and behavioral intention toward engagement with their sons, including assisting with HIV testing. However, what about parental involvement in these types of dialogues with children who have not yet come out to their parents?
Dr. Flores said that, although Dr. Huebner’s work is pivotal for families where the child’s sexual orientation is known to parents, there is value in inclusive sex communication for all youth, regardless of how they identify (that is, out of the closet, closeted, straight, or those who are questioning their identity), especially since younger generations of LGBTQ youth are coming out at earlier ages, compared with previous generations.
It’s not just parents. Clinicians also have critical roles to play in helping bridge the sex-talk communication gaps between parents and adolescents and young adult children.
“In my work, I’ve found that more clinicians are willing to broach this within the discussion with dyads, with parents and adolescents in the room,” said Dr. Flores.
And he added: “If clinicians signal that there’s no such thing as too early to have these conversations or that issues such as consent, safety, and sexting are all okay to talk about because these are the current realities of young people, then parents can feel that they’re empowered to broach or sustain these conversations.”
Importantly, Dr. Huebner and associates are currently recruiting larger numbers of families for a new, yearlong trial that will not only examine parental behavior changes but also whether these changes translate into improvements in their child’s sexual health and/or competency. Interested families can learn more about the study and sign up to receive updates at www.parentwithlove.org.
Dr. Huebner and Dr. Flores reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AIDS AND BEHAVIOR
Bepirovirsen: Is a ‘functional cure’ for HBV on the horizon?
Treatment with bepirovirsen led to sustained clearance of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA for 24 weeks after the end of treatment for adults with chronic HBV in the phase 2b B-Clear study.
The study results were presented at the annual meeting of the American Association for the Study of Liver Diseases and were simultaneously published in The New England Journal of Medicine.
Currently, nucleoside/nucleotide analogue (NA) therapy is the recommended first-line therapy for patients with chronic HBV because it can inhibit viral replication.
However, fewer than 5% of patients have HBsAg loss after 12 months of NA therapy, which underscores the need for therapies that can achieve a “functional” cure, largely defined as sustained, undetectable levels of HBV DNA and HBsAg in the blood, with or without generation of protective antibodies against HBsAg, the researchers noted.
Bepirovirsen is a potential first-in-class antisense oligonucleotide that targets all HBV messenger RNA and acts to decrease levels of viral proteins.
The phase 2b B-Clear study enrolled 457 patients with chronic HBV; 227 were receiving NA therapy, and 230 were not.
Participants were randomly assigned to receive weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks; bepirovirsen 300 mg for 12 weeks, then 150 mg for 12 weeks; bepirovirsen 300 mg for 12 weeks, then placebo for 12 weeks; or placebo for 12 weeks, then bepirovirsen 300 mg for 12 weeks (groups 1, 2, 3, and 4, respectively).
The composite primary outcome was HBsAg level below the limit of detection and HBV DNA level below the limit of quantification maintained for 24 weeks after the end of bepirovirsen treatment, without newly initiated antiviral medication.
Bepirovirsen 300 mg weekly for 24 weeks (group 1) led to HBsAg and HBV DNA loss in 9% of patients receiving NA therapy and 10% of patients not receiving NA treatment, which was sustained for 24 weeks after the last dose.
For groups 2, 3, and 4, HBsAg and HBV DNA loss occurred in 9%, 3%, and 0%, respectively, of patients receiving NA therapy and 6%, 1%, and 0%, respectively, of patients not receiving NA treatment.
Patients with low baseline HBsAg levels (< 1,000 IU/mL) responded best to treatment with bepirovirsen. Among patients who received bepirovirsen 300 mg weekly for 24 weeks, the primary outcome was achieved by 16% of patients taking NA therapy and by 25% of patients not taking NA therapy.
Although a “relatively low percentage” of patients overall achieved the primary outcome, the study “indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both,” the researchers wrote.
Adverse events with bepirovirsen included injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase (ALT) levels. Increases in ALT levels, which were more common in those not receiving NA therapy than in those receiving NA therapy (41% vs. 17%), led to two serious adverse events.
On the basis of phase 2b data, GlaxoSmithKline (GSK) plans to advance bepirovirsen into phase 3 development, according to a news release.
Further pursuit of bepirovirsen therapy is “certainly warranted, with the use of a dose of 300 mg per week for at least 24 weeks; indeed, the duration of therapy might be dictated best by HBsAg levels at baseline,” Jay H. Hoofnagle, MD, director of the liver disease research branch at the National Institute of Diabetes and Digestive and Kidney Diseases, wrote in an editorial in the New England Journal of Medicine.
Several critical questions remain, including whether HBsAg negativity will persist beyond 24 weeks, wrote Dr. Hoofnagle, who was not involved in the study.
It’s a question GSK is addressing in the B-Sure trial, which will follow participants for an additional 33 months, the study noted.
Other questions include when NA therapy can be safely stopped, what other factors predict response, and whether RNA therapy–induced loss of HBsAg materially improves long-term outcomes, Dr. Hoofnagle wrote.
“Bepirovirsen is just one RNA-based HBV therapy now being pursued. Several other antisense RNAs as well as the more malleable small interfering RNA molecules (‘-sirans’) are currently in early-phase clinical trials. A new era in the control of hepatitis B may be at hand with these most modern of therapies for this most ancient disease,” Dr. Hoofnagle noted.
The B-Clear study was supported by GSK. Several authors have disclosed relationships with the company. A complete list of author disclosures is available with the original article. Dr. Hoofnagle has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treatment with bepirovirsen led to sustained clearance of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA for 24 weeks after the end of treatment for adults with chronic HBV in the phase 2b B-Clear study.
The study results were presented at the annual meeting of the American Association for the Study of Liver Diseases and were simultaneously published in The New England Journal of Medicine.
Currently, nucleoside/nucleotide analogue (NA) therapy is the recommended first-line therapy for patients with chronic HBV because it can inhibit viral replication.
However, fewer than 5% of patients have HBsAg loss after 12 months of NA therapy, which underscores the need for therapies that can achieve a “functional” cure, largely defined as sustained, undetectable levels of HBV DNA and HBsAg in the blood, with or without generation of protective antibodies against HBsAg, the researchers noted.
Bepirovirsen is a potential first-in-class antisense oligonucleotide that targets all HBV messenger RNA and acts to decrease levels of viral proteins.
The phase 2b B-Clear study enrolled 457 patients with chronic HBV; 227 were receiving NA therapy, and 230 were not.
Participants were randomly assigned to receive weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks; bepirovirsen 300 mg for 12 weeks, then 150 mg for 12 weeks; bepirovirsen 300 mg for 12 weeks, then placebo for 12 weeks; or placebo for 12 weeks, then bepirovirsen 300 mg for 12 weeks (groups 1, 2, 3, and 4, respectively).
The composite primary outcome was HBsAg level below the limit of detection and HBV DNA level below the limit of quantification maintained for 24 weeks after the end of bepirovirsen treatment, without newly initiated antiviral medication.
Bepirovirsen 300 mg weekly for 24 weeks (group 1) led to HBsAg and HBV DNA loss in 9% of patients receiving NA therapy and 10% of patients not receiving NA treatment, which was sustained for 24 weeks after the last dose.
For groups 2, 3, and 4, HBsAg and HBV DNA loss occurred in 9%, 3%, and 0%, respectively, of patients receiving NA therapy and 6%, 1%, and 0%, respectively, of patients not receiving NA treatment.
Patients with low baseline HBsAg levels (< 1,000 IU/mL) responded best to treatment with bepirovirsen. Among patients who received bepirovirsen 300 mg weekly for 24 weeks, the primary outcome was achieved by 16% of patients taking NA therapy and by 25% of patients not taking NA therapy.
Although a “relatively low percentage” of patients overall achieved the primary outcome, the study “indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both,” the researchers wrote.
Adverse events with bepirovirsen included injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase (ALT) levels. Increases in ALT levels, which were more common in those not receiving NA therapy than in those receiving NA therapy (41% vs. 17%), led to two serious adverse events.
On the basis of phase 2b data, GlaxoSmithKline (GSK) plans to advance bepirovirsen into phase 3 development, according to a news release.
Further pursuit of bepirovirsen therapy is “certainly warranted, with the use of a dose of 300 mg per week for at least 24 weeks; indeed, the duration of therapy might be dictated best by HBsAg levels at baseline,” Jay H. Hoofnagle, MD, director of the liver disease research branch at the National Institute of Diabetes and Digestive and Kidney Diseases, wrote in an editorial in the New England Journal of Medicine.
Several critical questions remain, including whether HBsAg negativity will persist beyond 24 weeks, wrote Dr. Hoofnagle, who was not involved in the study.
It’s a question GSK is addressing in the B-Sure trial, which will follow participants for an additional 33 months, the study noted.
Other questions include when NA therapy can be safely stopped, what other factors predict response, and whether RNA therapy–induced loss of HBsAg materially improves long-term outcomes, Dr. Hoofnagle wrote.
“Bepirovirsen is just one RNA-based HBV therapy now being pursued. Several other antisense RNAs as well as the more malleable small interfering RNA molecules (‘-sirans’) are currently in early-phase clinical trials. A new era in the control of hepatitis B may be at hand with these most modern of therapies for this most ancient disease,” Dr. Hoofnagle noted.
The B-Clear study was supported by GSK. Several authors have disclosed relationships with the company. A complete list of author disclosures is available with the original article. Dr. Hoofnagle has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treatment with bepirovirsen led to sustained clearance of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA for 24 weeks after the end of treatment for adults with chronic HBV in the phase 2b B-Clear study.
The study results were presented at the annual meeting of the American Association for the Study of Liver Diseases and were simultaneously published in The New England Journal of Medicine.
Currently, nucleoside/nucleotide analogue (NA) therapy is the recommended first-line therapy for patients with chronic HBV because it can inhibit viral replication.
However, fewer than 5% of patients have HBsAg loss after 12 months of NA therapy, which underscores the need for therapies that can achieve a “functional” cure, largely defined as sustained, undetectable levels of HBV DNA and HBsAg in the blood, with or without generation of protective antibodies against HBsAg, the researchers noted.
Bepirovirsen is a potential first-in-class antisense oligonucleotide that targets all HBV messenger RNA and acts to decrease levels of viral proteins.
The phase 2b B-Clear study enrolled 457 patients with chronic HBV; 227 were receiving NA therapy, and 230 were not.
Participants were randomly assigned to receive weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks; bepirovirsen 300 mg for 12 weeks, then 150 mg for 12 weeks; bepirovirsen 300 mg for 12 weeks, then placebo for 12 weeks; or placebo for 12 weeks, then bepirovirsen 300 mg for 12 weeks (groups 1, 2, 3, and 4, respectively).
The composite primary outcome was HBsAg level below the limit of detection and HBV DNA level below the limit of quantification maintained for 24 weeks after the end of bepirovirsen treatment, without newly initiated antiviral medication.
Bepirovirsen 300 mg weekly for 24 weeks (group 1) led to HBsAg and HBV DNA loss in 9% of patients receiving NA therapy and 10% of patients not receiving NA treatment, which was sustained for 24 weeks after the last dose.
For groups 2, 3, and 4, HBsAg and HBV DNA loss occurred in 9%, 3%, and 0%, respectively, of patients receiving NA therapy and 6%, 1%, and 0%, respectively, of patients not receiving NA treatment.
Patients with low baseline HBsAg levels (< 1,000 IU/mL) responded best to treatment with bepirovirsen. Among patients who received bepirovirsen 300 mg weekly for 24 weeks, the primary outcome was achieved by 16% of patients taking NA therapy and by 25% of patients not taking NA therapy.
Although a “relatively low percentage” of patients overall achieved the primary outcome, the study “indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both,” the researchers wrote.
Adverse events with bepirovirsen included injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase (ALT) levels. Increases in ALT levels, which were more common in those not receiving NA therapy than in those receiving NA therapy (41% vs. 17%), led to two serious adverse events.
On the basis of phase 2b data, GlaxoSmithKline (GSK) plans to advance bepirovirsen into phase 3 development, according to a news release.
Further pursuit of bepirovirsen therapy is “certainly warranted, with the use of a dose of 300 mg per week for at least 24 weeks; indeed, the duration of therapy might be dictated best by HBsAg levels at baseline,” Jay H. Hoofnagle, MD, director of the liver disease research branch at the National Institute of Diabetes and Digestive and Kidney Diseases, wrote in an editorial in the New England Journal of Medicine.
Several critical questions remain, including whether HBsAg negativity will persist beyond 24 weeks, wrote Dr. Hoofnagle, who was not involved in the study.
It’s a question GSK is addressing in the B-Sure trial, which will follow participants for an additional 33 months, the study noted.
Other questions include when NA therapy can be safely stopped, what other factors predict response, and whether RNA therapy–induced loss of HBsAg materially improves long-term outcomes, Dr. Hoofnagle wrote.
“Bepirovirsen is just one RNA-based HBV therapy now being pursued. Several other antisense RNAs as well as the more malleable small interfering RNA molecules (‘-sirans’) are currently in early-phase clinical trials. A new era in the control of hepatitis B may be at hand with these most modern of therapies for this most ancient disease,” Dr. Hoofnagle noted.
The B-Clear study was supported by GSK. Several authors have disclosed relationships with the company. A complete list of author disclosures is available with the original article. Dr. Hoofnagle has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LIVER MEETING