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Liquid biopsy assay can predict CRC recurrence early
A (CRC).
Patients who were ctDNA methylation positive 1 month after surgery were 17.5 times more likely to relapse, compared with ctDNA-negative patients. And following adjuvant chemotherapy, ctDNA-positive patients had a significantly shorter recurrence-free survival than their ctDNA-negative peers.
Overall, “we found that ctDNA methylation was the most significant prognostic factor for recurrence-free survival among all clinicopathologic risk factors on multivariable analysis,” the authors, led by Shaobo Mo, MD, Fudan University Shanghai (China) Cancer Center, reported in research published in JAMA Oncology.
Van Morris, MD, an oncologist with University of Texas MD Anderson Cancer Center, Houston, who was not involved in the research, noted that other commercially available ctDNA assays have achieved similar findings, but this assay involves the least number of biomarkers.
More notably, the broader message emerging from this research is that “ctDNA is a powerful tool in oncology that is here to stay,” said Dr. Morris.
Dr. Morris added a note of caution, however: Despite the study providing further support for this technology in CRC, “we do not have definitive predictive utility for routinely guiding adjuvant chemotherapy decisions with the use of this [or other] ctDNA assays.”
Recurrence common, predictors important
CRC has a relatively high recurrence rate even after curative-intent therapies, with a 5-year survival rate as low as 60%. Adjuvant chemotherapy in patients with stage III CRC generally lowers the risk of recurrence by about 10%-20%; however, the benefits of adjuvant chemotherapy among patients with stage II CRC remain unclear.
Strategies to identify patients most likely to relapse after adjuvant therapy largely focus on CRC stage and clinical risk factors, though postoperative ctDNA testing has emerged as a tool to help identify patients at risk for recurrence. Often, however, this approach involves ultradeep next-generation sequencing, which limits the strategy’s ease of implementation and cost effectiveness.
As an alternative, the authors used a plasma ctDNA methylation test, ColonAiQ, which identifies the presence of six genomic biomarkers hypermethylated in CRC. This test avoids the complex process of primary tumor profiling among individual patients.
In the multicenter, prospective longitudinal cohort study, conducted from December 2019 to February 2022, Dr. Mo and colleagues evaluated 1,228 blood samples from 299 patients with stage I-III CRC. Samples were collected before and after surgery, during and after adjuvant chemotherapy, and every 3 months for up to 2 years.
Of 296 patients with preoperative samples available, as many as 232 (78.4%) tested positive for at least one of the 6 ctDNA methylation markers. The detection rates were 65.1% for stage I CRC, 82.7% for stage II disease, and 81.5% for stage III disease.
At postoperative month 1, ctDNA methylation–positive patients were 17.5 times more likely to relapse, compared with ctDNA-negative patients (hazard ratio, 17.5; P < .001).
When integrating carcinoembryonic antigen testing alongside ctDNA testing, patients with positive test results had significantly worse prognoses, compared with those who had negative results (HR, 19.0; P < .001).
The association of ctDNA methylation positivity at postoperative month 1 and CRC recurrence was consistent across varying durations and intensities of adjuvant chemotherapy. The researchers found that ctDNA methylation analysis detected CRC recurrence a median of 3.3 months earlier than radiologically confirmed recurrence.
Patients who were ctDNA positive also had significantly shorter periods of recurrence-free survival following adjuvant chemotherapy, compared with ctDNA-negative patients (HR, 13.8; P < .001). That effect was enhanced when positive ctDNA status was maintained longitudinally, compared with those who were persistently ctDNA negative (HR, 68.8; P < .001).
More specifically, 140 patients exhibited sustained ctDNA-positive status over time; 6 of 7 ctDNA-positive patients experienced recurrence within 12 months, whereas 129 of 133 ctDNA-negative patients (97%) remained relapse free. And being ctDNA negative before surgery indicated patients’ relapse risk, with 95.3% of patients who were ctDNA negative presurgery remaining relapse free.
Dr. Mo and colleagues concluded that the simplicity of the assay work flow and convenience of taking blood samples make this approach practical and cost effective in the clinical setting.
In an editorial published alongside the study, Juan Ruiz-Bañobre, MD, PhD, and Ajay Goel, PhD, noted that the field is evolving rapidly but “there is substantial value in prospectively validating the clinical importance of ColonAiQ in randomized clinical trials.”
“If successful, this liquid biopsy assay could represent a simple and cost-effective means for a more accessible and facile decentralized implementation in routine clinical practice,” said Dr. Ruiz-Bañobre, of the University of Santiago de Compostela, A Coruña, Spain, and Dr. Goel, from City of Hope Comprehensive Cancer Center in Duarte, Calif.
Several of the study coauthors are employees of Singlera Genomics, which makes the ColonAiQ test. Dr. Ruiz-Bañobre reported grants from the Spanish Cooperative Group for the Treatment of Digestive Tumors and support from Institute of Health Carlos III. Dr. Morris is the principal investigator on the NRG GI005 trial of the Guardant Reveal liquid biopsy, sponsored by Guardant Health in collaboration with funding support from the National Cancer Institute.
A version of this article first appeared on Medscape.com.
A (CRC).
Patients who were ctDNA methylation positive 1 month after surgery were 17.5 times more likely to relapse, compared with ctDNA-negative patients. And following adjuvant chemotherapy, ctDNA-positive patients had a significantly shorter recurrence-free survival than their ctDNA-negative peers.
Overall, “we found that ctDNA methylation was the most significant prognostic factor for recurrence-free survival among all clinicopathologic risk factors on multivariable analysis,” the authors, led by Shaobo Mo, MD, Fudan University Shanghai (China) Cancer Center, reported in research published in JAMA Oncology.
Van Morris, MD, an oncologist with University of Texas MD Anderson Cancer Center, Houston, who was not involved in the research, noted that other commercially available ctDNA assays have achieved similar findings, but this assay involves the least number of biomarkers.
More notably, the broader message emerging from this research is that “ctDNA is a powerful tool in oncology that is here to stay,” said Dr. Morris.
Dr. Morris added a note of caution, however: Despite the study providing further support for this technology in CRC, “we do not have definitive predictive utility for routinely guiding adjuvant chemotherapy decisions with the use of this [or other] ctDNA assays.”
Recurrence common, predictors important
CRC has a relatively high recurrence rate even after curative-intent therapies, with a 5-year survival rate as low as 60%. Adjuvant chemotherapy in patients with stage III CRC generally lowers the risk of recurrence by about 10%-20%; however, the benefits of adjuvant chemotherapy among patients with stage II CRC remain unclear.
Strategies to identify patients most likely to relapse after adjuvant therapy largely focus on CRC stage and clinical risk factors, though postoperative ctDNA testing has emerged as a tool to help identify patients at risk for recurrence. Often, however, this approach involves ultradeep next-generation sequencing, which limits the strategy’s ease of implementation and cost effectiveness.
As an alternative, the authors used a plasma ctDNA methylation test, ColonAiQ, which identifies the presence of six genomic biomarkers hypermethylated in CRC. This test avoids the complex process of primary tumor profiling among individual patients.
In the multicenter, prospective longitudinal cohort study, conducted from December 2019 to February 2022, Dr. Mo and colleagues evaluated 1,228 blood samples from 299 patients with stage I-III CRC. Samples were collected before and after surgery, during and after adjuvant chemotherapy, and every 3 months for up to 2 years.
Of 296 patients with preoperative samples available, as many as 232 (78.4%) tested positive for at least one of the 6 ctDNA methylation markers. The detection rates were 65.1% for stage I CRC, 82.7% for stage II disease, and 81.5% for stage III disease.
At postoperative month 1, ctDNA methylation–positive patients were 17.5 times more likely to relapse, compared with ctDNA-negative patients (hazard ratio, 17.5; P < .001).
When integrating carcinoembryonic antigen testing alongside ctDNA testing, patients with positive test results had significantly worse prognoses, compared with those who had negative results (HR, 19.0; P < .001).
The association of ctDNA methylation positivity at postoperative month 1 and CRC recurrence was consistent across varying durations and intensities of adjuvant chemotherapy. The researchers found that ctDNA methylation analysis detected CRC recurrence a median of 3.3 months earlier than radiologically confirmed recurrence.
Patients who were ctDNA positive also had significantly shorter periods of recurrence-free survival following adjuvant chemotherapy, compared with ctDNA-negative patients (HR, 13.8; P < .001). That effect was enhanced when positive ctDNA status was maintained longitudinally, compared with those who were persistently ctDNA negative (HR, 68.8; P < .001).
More specifically, 140 patients exhibited sustained ctDNA-positive status over time; 6 of 7 ctDNA-positive patients experienced recurrence within 12 months, whereas 129 of 133 ctDNA-negative patients (97%) remained relapse free. And being ctDNA negative before surgery indicated patients’ relapse risk, with 95.3% of patients who were ctDNA negative presurgery remaining relapse free.
Dr. Mo and colleagues concluded that the simplicity of the assay work flow and convenience of taking blood samples make this approach practical and cost effective in the clinical setting.
In an editorial published alongside the study, Juan Ruiz-Bañobre, MD, PhD, and Ajay Goel, PhD, noted that the field is evolving rapidly but “there is substantial value in prospectively validating the clinical importance of ColonAiQ in randomized clinical trials.”
“If successful, this liquid biopsy assay could represent a simple and cost-effective means for a more accessible and facile decentralized implementation in routine clinical practice,” said Dr. Ruiz-Bañobre, of the University of Santiago de Compostela, A Coruña, Spain, and Dr. Goel, from City of Hope Comprehensive Cancer Center in Duarte, Calif.
Several of the study coauthors are employees of Singlera Genomics, which makes the ColonAiQ test. Dr. Ruiz-Bañobre reported grants from the Spanish Cooperative Group for the Treatment of Digestive Tumors and support from Institute of Health Carlos III. Dr. Morris is the principal investigator on the NRG GI005 trial of the Guardant Reveal liquid biopsy, sponsored by Guardant Health in collaboration with funding support from the National Cancer Institute.
A version of this article first appeared on Medscape.com.
A (CRC).
Patients who were ctDNA methylation positive 1 month after surgery were 17.5 times more likely to relapse, compared with ctDNA-negative patients. And following adjuvant chemotherapy, ctDNA-positive patients had a significantly shorter recurrence-free survival than their ctDNA-negative peers.
Overall, “we found that ctDNA methylation was the most significant prognostic factor for recurrence-free survival among all clinicopathologic risk factors on multivariable analysis,” the authors, led by Shaobo Mo, MD, Fudan University Shanghai (China) Cancer Center, reported in research published in JAMA Oncology.
Van Morris, MD, an oncologist with University of Texas MD Anderson Cancer Center, Houston, who was not involved in the research, noted that other commercially available ctDNA assays have achieved similar findings, but this assay involves the least number of biomarkers.
More notably, the broader message emerging from this research is that “ctDNA is a powerful tool in oncology that is here to stay,” said Dr. Morris.
Dr. Morris added a note of caution, however: Despite the study providing further support for this technology in CRC, “we do not have definitive predictive utility for routinely guiding adjuvant chemotherapy decisions with the use of this [or other] ctDNA assays.”
Recurrence common, predictors important
CRC has a relatively high recurrence rate even after curative-intent therapies, with a 5-year survival rate as low as 60%. Adjuvant chemotherapy in patients with stage III CRC generally lowers the risk of recurrence by about 10%-20%; however, the benefits of adjuvant chemotherapy among patients with stage II CRC remain unclear.
Strategies to identify patients most likely to relapse after adjuvant therapy largely focus on CRC stage and clinical risk factors, though postoperative ctDNA testing has emerged as a tool to help identify patients at risk for recurrence. Often, however, this approach involves ultradeep next-generation sequencing, which limits the strategy’s ease of implementation and cost effectiveness.
As an alternative, the authors used a plasma ctDNA methylation test, ColonAiQ, which identifies the presence of six genomic biomarkers hypermethylated in CRC. This test avoids the complex process of primary tumor profiling among individual patients.
In the multicenter, prospective longitudinal cohort study, conducted from December 2019 to February 2022, Dr. Mo and colleagues evaluated 1,228 blood samples from 299 patients with stage I-III CRC. Samples were collected before and after surgery, during and after adjuvant chemotherapy, and every 3 months for up to 2 years.
Of 296 patients with preoperative samples available, as many as 232 (78.4%) tested positive for at least one of the 6 ctDNA methylation markers. The detection rates were 65.1% for stage I CRC, 82.7% for stage II disease, and 81.5% for stage III disease.
At postoperative month 1, ctDNA methylation–positive patients were 17.5 times more likely to relapse, compared with ctDNA-negative patients (hazard ratio, 17.5; P < .001).
When integrating carcinoembryonic antigen testing alongside ctDNA testing, patients with positive test results had significantly worse prognoses, compared with those who had negative results (HR, 19.0; P < .001).
The association of ctDNA methylation positivity at postoperative month 1 and CRC recurrence was consistent across varying durations and intensities of adjuvant chemotherapy. The researchers found that ctDNA methylation analysis detected CRC recurrence a median of 3.3 months earlier than radiologically confirmed recurrence.
Patients who were ctDNA positive also had significantly shorter periods of recurrence-free survival following adjuvant chemotherapy, compared with ctDNA-negative patients (HR, 13.8; P < .001). That effect was enhanced when positive ctDNA status was maintained longitudinally, compared with those who were persistently ctDNA negative (HR, 68.8; P < .001).
More specifically, 140 patients exhibited sustained ctDNA-positive status over time; 6 of 7 ctDNA-positive patients experienced recurrence within 12 months, whereas 129 of 133 ctDNA-negative patients (97%) remained relapse free. And being ctDNA negative before surgery indicated patients’ relapse risk, with 95.3% of patients who were ctDNA negative presurgery remaining relapse free.
Dr. Mo and colleagues concluded that the simplicity of the assay work flow and convenience of taking blood samples make this approach practical and cost effective in the clinical setting.
In an editorial published alongside the study, Juan Ruiz-Bañobre, MD, PhD, and Ajay Goel, PhD, noted that the field is evolving rapidly but “there is substantial value in prospectively validating the clinical importance of ColonAiQ in randomized clinical trials.”
“If successful, this liquid biopsy assay could represent a simple and cost-effective means for a more accessible and facile decentralized implementation in routine clinical practice,” said Dr. Ruiz-Bañobre, of the University of Santiago de Compostela, A Coruña, Spain, and Dr. Goel, from City of Hope Comprehensive Cancer Center in Duarte, Calif.
Several of the study coauthors are employees of Singlera Genomics, which makes the ColonAiQ test. Dr. Ruiz-Bañobre reported grants from the Spanish Cooperative Group for the Treatment of Digestive Tumors and support from Institute of Health Carlos III. Dr. Morris is the principal investigator on the NRG GI005 trial of the Guardant Reveal liquid biopsy, sponsored by Guardant Health in collaboration with funding support from the National Cancer Institute.
A version of this article first appeared on Medscape.com.
FROM JAMA ONCOLOGY
Weight loss linked to early death in older but healthy adults
suggesting the need for clinicians to be alert to such changes.
“Our study emphasizes the importance of weight loss even in relatively healthy individuals who are free from evident cardiovascular disease [CVD], dementia, physical disability, or life-limiting chronic illness,” first author Monira Hussain, MBBS, MPH, PhD, said in an interview.
“Clinicians should be aware that even minor weight loss of 5% or more in older adults without life-limiting illnesses can increase mortality risk,” Dr. Hussain said. “Regular monitoring of weight changes can help early identification of associated risks.”
The study was published online in JAMA Network Open.
The researchers noted that data on the significance of weight changes among older individuals who are otherwise relatively healthy and not diagnosed with life-limited diseases are limited, with the exception that “it is widely acknowledged that weight loss may precede a diagnosis of cancer.” But the association with the other types of non–cancer-related premature death is notable.
“In our study, weight loss also preceded an increased mortality from CVD and other causes, [such as] deaths from trauma, dementia, Parkinson disease, and other less common causes.”
Therefore, “a likely explanation for these findings is that weight loss can be an early prodromal indicator of the presence of various life-shortening diseases,” Dr. Hussain, of Monash University, Melbourne, and colleagues wrote.
In terms of why weight loss shows such a stronger link to mortality in older men, compared with women, Dr. Hussain speculated that this may be caused by “differences in body composition,” between the two sexes. “Men have a higher proportion of muscle and bone mass, and weight loss [in men] primarily involves loss of these tissues.”
10% weight loss quadrupled risk of premature death among men
To investigate this phenomenon, the researchers conducted a post hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial, which included information on a variety of body size parameters, such as weight and waist circumference, measured annually, from a large population of healthy individuals with no evident CVD, dementia, physical disability, or life-limiting chronic illness.
The 16,523 participants included in the study had a mean age of 75 years and 55.6% were women. During a mean follow-up of 4.4 years, 1,256 deaths occurred in the cohort.
Looking at rates of all-cause mortality, stratified by gender, the results showed that among men who had a 5%-10% decrease in weight over the course of the study, the risk of all-cause mortality was 33% higher than that of men who had a stable weight (less than 5% change; hazard ratio, 1.33).
Among men who had a more than 10% decrease in weight, the mortality risk was as much as 289%, or nearly four times higher compared with those with a stable weight (HR, 3.89).
For women, the mortality risk was also increased, however, to a lesser degree. A 5%-10% loss of body weight was associated with a 26% increased mortality risk (HR, 1.26), and a loss of more than 10% was linked to a 114% increased risk of all-cause mortality (HR, 2.14).
In terms of cancer-specific deaths, the risk was significantly increased only among men who had a greater than 10% weight decrease (HR, 3.49), while the increased risk in women was observed with a 5%-10% decrease in weight (HR, 1.44) as well as a more than 10% decrease (HR, 2.78).
The risk of CVD-specific death was significantly increased with a more than 10% decrease in weight in both sexes, but the risk was again higher among men (HR, 3.14) than women (HR, 1.92), compared with stable weight groups.
And the noncancer, non–CVD-specific mortality risk was nearly five times higher among men who had a more than 10% decrease in weight versus stable weight (HR, 4.98); however, the association was not significant among women (HR, 1.49).
Looking at the effects of change in waist circumference, a decrease of more than 10% was associated with a higher risk in all-cause mortality that was again higher for men (HR, 2.14) versus women (HR, 1.34); however, no link with all-cause mortality was observed with a less than 10% decrease in either sex.
A greater than 10% decrease in waist circumference was also associated with higher risk of cancer death for men and women, and higher noncancer, non-CVD death among men, but not women, while there was no association between waist circumference and CVD mortality in men or women.
Association with mortality remained after adjustment for hospitalization
The results persisted after adjustment for age, frailty status, baseline body mass index, country of birth, smoking, hypertension, diabetes, and hospitalization in the previous 24 months.
The adjustment for recent hospitalization was especially important for ruling out weight loss that may have occurred because of hospitalization for acute conditions that could have contributed to mortality, the authors noted.
The authors reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
suggesting the need for clinicians to be alert to such changes.
“Our study emphasizes the importance of weight loss even in relatively healthy individuals who are free from evident cardiovascular disease [CVD], dementia, physical disability, or life-limiting chronic illness,” first author Monira Hussain, MBBS, MPH, PhD, said in an interview.
“Clinicians should be aware that even minor weight loss of 5% or more in older adults without life-limiting illnesses can increase mortality risk,” Dr. Hussain said. “Regular monitoring of weight changes can help early identification of associated risks.”
The study was published online in JAMA Network Open.
The researchers noted that data on the significance of weight changes among older individuals who are otherwise relatively healthy and not diagnosed with life-limited diseases are limited, with the exception that “it is widely acknowledged that weight loss may precede a diagnosis of cancer.” But the association with the other types of non–cancer-related premature death is notable.
“In our study, weight loss also preceded an increased mortality from CVD and other causes, [such as] deaths from trauma, dementia, Parkinson disease, and other less common causes.”
Therefore, “a likely explanation for these findings is that weight loss can be an early prodromal indicator of the presence of various life-shortening diseases,” Dr. Hussain, of Monash University, Melbourne, and colleagues wrote.
In terms of why weight loss shows such a stronger link to mortality in older men, compared with women, Dr. Hussain speculated that this may be caused by “differences in body composition,” between the two sexes. “Men have a higher proportion of muscle and bone mass, and weight loss [in men] primarily involves loss of these tissues.”
10% weight loss quadrupled risk of premature death among men
To investigate this phenomenon, the researchers conducted a post hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial, which included information on a variety of body size parameters, such as weight and waist circumference, measured annually, from a large population of healthy individuals with no evident CVD, dementia, physical disability, or life-limiting chronic illness.
The 16,523 participants included in the study had a mean age of 75 years and 55.6% were women. During a mean follow-up of 4.4 years, 1,256 deaths occurred in the cohort.
Looking at rates of all-cause mortality, stratified by gender, the results showed that among men who had a 5%-10% decrease in weight over the course of the study, the risk of all-cause mortality was 33% higher than that of men who had a stable weight (less than 5% change; hazard ratio, 1.33).
Among men who had a more than 10% decrease in weight, the mortality risk was as much as 289%, or nearly four times higher compared with those with a stable weight (HR, 3.89).
For women, the mortality risk was also increased, however, to a lesser degree. A 5%-10% loss of body weight was associated with a 26% increased mortality risk (HR, 1.26), and a loss of more than 10% was linked to a 114% increased risk of all-cause mortality (HR, 2.14).
In terms of cancer-specific deaths, the risk was significantly increased only among men who had a greater than 10% weight decrease (HR, 3.49), while the increased risk in women was observed with a 5%-10% decrease in weight (HR, 1.44) as well as a more than 10% decrease (HR, 2.78).
The risk of CVD-specific death was significantly increased with a more than 10% decrease in weight in both sexes, but the risk was again higher among men (HR, 3.14) than women (HR, 1.92), compared with stable weight groups.
And the noncancer, non–CVD-specific mortality risk was nearly five times higher among men who had a more than 10% decrease in weight versus stable weight (HR, 4.98); however, the association was not significant among women (HR, 1.49).
Looking at the effects of change in waist circumference, a decrease of more than 10% was associated with a higher risk in all-cause mortality that was again higher for men (HR, 2.14) versus women (HR, 1.34); however, no link with all-cause mortality was observed with a less than 10% decrease in either sex.
A greater than 10% decrease in waist circumference was also associated with higher risk of cancer death for men and women, and higher noncancer, non-CVD death among men, but not women, while there was no association between waist circumference and CVD mortality in men or women.
Association with mortality remained after adjustment for hospitalization
The results persisted after adjustment for age, frailty status, baseline body mass index, country of birth, smoking, hypertension, diabetes, and hospitalization in the previous 24 months.
The adjustment for recent hospitalization was especially important for ruling out weight loss that may have occurred because of hospitalization for acute conditions that could have contributed to mortality, the authors noted.
The authors reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
suggesting the need for clinicians to be alert to such changes.
“Our study emphasizes the importance of weight loss even in relatively healthy individuals who are free from evident cardiovascular disease [CVD], dementia, physical disability, or life-limiting chronic illness,” first author Monira Hussain, MBBS, MPH, PhD, said in an interview.
“Clinicians should be aware that even minor weight loss of 5% or more in older adults without life-limiting illnesses can increase mortality risk,” Dr. Hussain said. “Regular monitoring of weight changes can help early identification of associated risks.”
The study was published online in JAMA Network Open.
The researchers noted that data on the significance of weight changes among older individuals who are otherwise relatively healthy and not diagnosed with life-limited diseases are limited, with the exception that “it is widely acknowledged that weight loss may precede a diagnosis of cancer.” But the association with the other types of non–cancer-related premature death is notable.
“In our study, weight loss also preceded an increased mortality from CVD and other causes, [such as] deaths from trauma, dementia, Parkinson disease, and other less common causes.”
Therefore, “a likely explanation for these findings is that weight loss can be an early prodromal indicator of the presence of various life-shortening diseases,” Dr. Hussain, of Monash University, Melbourne, and colleagues wrote.
In terms of why weight loss shows such a stronger link to mortality in older men, compared with women, Dr. Hussain speculated that this may be caused by “differences in body composition,” between the two sexes. “Men have a higher proportion of muscle and bone mass, and weight loss [in men] primarily involves loss of these tissues.”
10% weight loss quadrupled risk of premature death among men
To investigate this phenomenon, the researchers conducted a post hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial, which included information on a variety of body size parameters, such as weight and waist circumference, measured annually, from a large population of healthy individuals with no evident CVD, dementia, physical disability, or life-limiting chronic illness.
The 16,523 participants included in the study had a mean age of 75 years and 55.6% were women. During a mean follow-up of 4.4 years, 1,256 deaths occurred in the cohort.
Looking at rates of all-cause mortality, stratified by gender, the results showed that among men who had a 5%-10% decrease in weight over the course of the study, the risk of all-cause mortality was 33% higher than that of men who had a stable weight (less than 5% change; hazard ratio, 1.33).
Among men who had a more than 10% decrease in weight, the mortality risk was as much as 289%, or nearly four times higher compared with those with a stable weight (HR, 3.89).
For women, the mortality risk was also increased, however, to a lesser degree. A 5%-10% loss of body weight was associated with a 26% increased mortality risk (HR, 1.26), and a loss of more than 10% was linked to a 114% increased risk of all-cause mortality (HR, 2.14).
In terms of cancer-specific deaths, the risk was significantly increased only among men who had a greater than 10% weight decrease (HR, 3.49), while the increased risk in women was observed with a 5%-10% decrease in weight (HR, 1.44) as well as a more than 10% decrease (HR, 2.78).
The risk of CVD-specific death was significantly increased with a more than 10% decrease in weight in both sexes, but the risk was again higher among men (HR, 3.14) than women (HR, 1.92), compared with stable weight groups.
And the noncancer, non–CVD-specific mortality risk was nearly five times higher among men who had a more than 10% decrease in weight versus stable weight (HR, 4.98); however, the association was not significant among women (HR, 1.49).
Looking at the effects of change in waist circumference, a decrease of more than 10% was associated with a higher risk in all-cause mortality that was again higher for men (HR, 2.14) versus women (HR, 1.34); however, no link with all-cause mortality was observed with a less than 10% decrease in either sex.
A greater than 10% decrease in waist circumference was also associated with higher risk of cancer death for men and women, and higher noncancer, non-CVD death among men, but not women, while there was no association between waist circumference and CVD mortality in men or women.
Association with mortality remained after adjustment for hospitalization
The results persisted after adjustment for age, frailty status, baseline body mass index, country of birth, smoking, hypertension, diabetes, and hospitalization in the previous 24 months.
The adjustment for recent hospitalization was especially important for ruling out weight loss that may have occurred because of hospitalization for acute conditions that could have contributed to mortality, the authors noted.
The authors reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Breast conservation safe even with multiple-site tumors
BOSTON – , as new data show a low risk of recurrence at 5 years when they are treated with breast-conserving therapy and radiation.
“[The study] proves the oncologic safety of breast conservation in women with two or three sites of disease, making this a very reasonable option for (previously reluctant) surgeons to present to patients,” first author Kari Rosenkranz, MD, an associate professor at Dartmouth Health in Norwich, Vt., said in an interview.
The findings were presented here at the International Conference on Surgical Cancer Care (SSO 2023), and were published online in the Journal of Clinical Oncology.
Commenting on the study, Hiram S. Cody III, MD, an attending surgeon and professor of surgery at Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, in New York, said the findings provide valuable new evidence on the issue.
“This is an important study confirming that breast conservation is feasible and safe for women with multiple ipsilateral breast cancers, with excellent results comparable to those for women with unifocal (single site) disease,” he said in an interview.
Although there have been as many as seven previous randomized trials that have shown identical outcomes in survival and local control of disease with breast-conserving therapy versus mastectomy, all those studies excluded patients with more than one site of disease.
At present, many surgeons and guidelines continue to recommend mastectomy for women with multiple-site tumors, based on older data that showed higher recurrence rates.
That is why the new study is so important, Dr. Cody explained. “Here, we see in a prospective trial that breast-conserving therapy is feasible for those with more than one site of disease as well, with high survival and very low rates of local recurrence,” he emphasized.
Dr. Cody noted that “the ideal candidate would be a woman with relatively small tumor size and a breast large enough that the multiple excisions could be performed with a good cosmetic result.”
“We have followed this approach for some time and hope that with the publication of these results more surgeons will recommend this approach for suitable patients,” he said.
The new results were also highlighted in a press release from Mayo Clinic highlighting the Journal of Clinical Oncology publication. Lead author of the article, surgical oncologist Judy Boughey, MD, from the Mayo Clinic in Rochester, Minn., commented: “I am excited about these findings because it will empower patients and the multidisciplinary care teams caring for patients to be thinking about this option for women who may want to preserve their breast.”
This study showed the rate of cancer local recurrence was 3.1%, she noted. This is an excellent outcome and is similar to the local recurrence rate for patients with a single tumor in a breast who had breast-conserving therapy, Dr. Boughey said.
Historically, women with multiple tumors in one breast have been advised to have a mastectomy. Now, patients can be offered a less invasive option with faster recovery, resulting in better patient satisfaction and cosmetic outcomes, she added.
Study details
This study, known as the ACOSOG (Alliance) Z11102 trial, was a phase 2 trial conducted in 204 patients enrolled between 2012 and 2016 who had two or three sites of biopsy-proven breast cancer (each site less rhan 5 cm in size, with cN0 or cN1 disease).
These patients were a median age of 61 years, and 83.5% were ER-positive/HER2-negative, 11.5% were HER2-positive, 5.0% were ER-negative/HER2-negative, and 77.5% were node-negative.
All patients were treated with breast conservation surgery, including lumpectomy resected to negative margins, followed by whole breast radiation with a cavity boost to all lumpectomy beds.
With a median follow-up of 66.4 months, six patients developed local recurrence, with five of the recurrences occurring in the ipsilateral breast and one in the chest wall.
For the primary endpoint, the six recurrences represented an estimated cumulative incidence of local recurrence of 3.1% (95% CI, 1.3-6.4), well below the cutoff of 8% that was determined to be the acceptable 5-year local recurrence rate based on historic recurrence rates for unifocal disease, Dr. Rosenkranz explained.
There were no cases of synchronous local and distant recurrences, six contralateral breast cancers, and three new primary nonbreast cancers. Eight patients died, including one related to breast cancer.
There were no significant associations between risk of local recurrence and factors including patient age, number of sites of preoperative biopsy-proven breast cancer, HER2 status, and pathologic T and N category.
In terms of secondary endpoints, 14 patients (7.1%) converted to mastectomy because of positive margins, while 67.6% achieved margin-negative excision in a single operation.
Regarding cosmesis, 70.6% of patients reported good or excellent cosmetic outcomes at 2 years.
In terms of adherence, the whole breast radiation therapy protocol was feasible in most patients.
Of note, among patients without a breast preoperative MRI, the 5-year rate of local recurrence was significantly higher, at 22.6% (n = 14) at 5 years, compared with 1.7% among the 180 patients who did have a preoperative MRI (P = .002). However, Dr. Rosenkranz said these differences should be interpreted with caution.
“We may look at these data and think we should consider preoperative breast MRI in patients who do have known multiple ipsilateral breast cancer, although I think this cohort was certainly much too small to draw definitive conclusions, and this was not a planned secondary endpoint of the trial,” she said during her presentation.
Most prefer breast conservation, when possible
Overall, the findings are important considering the array of known benefits of breast conservation over mastectomy, Dr. Rosenkranz concluded.
“The reason this is so important is that we know that patients who undergo breast conservation report improved quality of life, self-esteem, and body image, and therefore it’s incumbent on us as surgeons to expand the indications for breast conservation where we can,” she told the audience.
Speaking with this news organization, she added that the decision-making around breast conservation versus mastectomy can be complicated, and some women do opt for mastectomy because of a variety of factors; therefore, “tailoring therapy to the individual goals and priorities in addition to the disease characteristics is critical.”
That said, she added that “the majority of patients who are eligible for breast conservation do prefer this option.”
Dr. Rosenkranz and Dr. Cody have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BOSTON – , as new data show a low risk of recurrence at 5 years when they are treated with breast-conserving therapy and radiation.
“[The study] proves the oncologic safety of breast conservation in women with two or three sites of disease, making this a very reasonable option for (previously reluctant) surgeons to present to patients,” first author Kari Rosenkranz, MD, an associate professor at Dartmouth Health in Norwich, Vt., said in an interview.
The findings were presented here at the International Conference on Surgical Cancer Care (SSO 2023), and were published online in the Journal of Clinical Oncology.
Commenting on the study, Hiram S. Cody III, MD, an attending surgeon and professor of surgery at Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, in New York, said the findings provide valuable new evidence on the issue.
“This is an important study confirming that breast conservation is feasible and safe for women with multiple ipsilateral breast cancers, with excellent results comparable to those for women with unifocal (single site) disease,” he said in an interview.
Although there have been as many as seven previous randomized trials that have shown identical outcomes in survival and local control of disease with breast-conserving therapy versus mastectomy, all those studies excluded patients with more than one site of disease.
At present, many surgeons and guidelines continue to recommend mastectomy for women with multiple-site tumors, based on older data that showed higher recurrence rates.
That is why the new study is so important, Dr. Cody explained. “Here, we see in a prospective trial that breast-conserving therapy is feasible for those with more than one site of disease as well, with high survival and very low rates of local recurrence,” he emphasized.
Dr. Cody noted that “the ideal candidate would be a woman with relatively small tumor size and a breast large enough that the multiple excisions could be performed with a good cosmetic result.”
“We have followed this approach for some time and hope that with the publication of these results more surgeons will recommend this approach for suitable patients,” he said.
The new results were also highlighted in a press release from Mayo Clinic highlighting the Journal of Clinical Oncology publication. Lead author of the article, surgical oncologist Judy Boughey, MD, from the Mayo Clinic in Rochester, Minn., commented: “I am excited about these findings because it will empower patients and the multidisciplinary care teams caring for patients to be thinking about this option for women who may want to preserve their breast.”
This study showed the rate of cancer local recurrence was 3.1%, she noted. This is an excellent outcome and is similar to the local recurrence rate for patients with a single tumor in a breast who had breast-conserving therapy, Dr. Boughey said.
Historically, women with multiple tumors in one breast have been advised to have a mastectomy. Now, patients can be offered a less invasive option with faster recovery, resulting in better patient satisfaction and cosmetic outcomes, she added.
Study details
This study, known as the ACOSOG (Alliance) Z11102 trial, was a phase 2 trial conducted in 204 patients enrolled between 2012 and 2016 who had two or three sites of biopsy-proven breast cancer (each site less rhan 5 cm in size, with cN0 or cN1 disease).
These patients were a median age of 61 years, and 83.5% were ER-positive/HER2-negative, 11.5% were HER2-positive, 5.0% were ER-negative/HER2-negative, and 77.5% were node-negative.
All patients were treated with breast conservation surgery, including lumpectomy resected to negative margins, followed by whole breast radiation with a cavity boost to all lumpectomy beds.
With a median follow-up of 66.4 months, six patients developed local recurrence, with five of the recurrences occurring in the ipsilateral breast and one in the chest wall.
For the primary endpoint, the six recurrences represented an estimated cumulative incidence of local recurrence of 3.1% (95% CI, 1.3-6.4), well below the cutoff of 8% that was determined to be the acceptable 5-year local recurrence rate based on historic recurrence rates for unifocal disease, Dr. Rosenkranz explained.
There were no cases of synchronous local and distant recurrences, six contralateral breast cancers, and three new primary nonbreast cancers. Eight patients died, including one related to breast cancer.
There were no significant associations between risk of local recurrence and factors including patient age, number of sites of preoperative biopsy-proven breast cancer, HER2 status, and pathologic T and N category.
In terms of secondary endpoints, 14 patients (7.1%) converted to mastectomy because of positive margins, while 67.6% achieved margin-negative excision in a single operation.
Regarding cosmesis, 70.6% of patients reported good or excellent cosmetic outcomes at 2 years.
In terms of adherence, the whole breast radiation therapy protocol was feasible in most patients.
Of note, among patients without a breast preoperative MRI, the 5-year rate of local recurrence was significantly higher, at 22.6% (n = 14) at 5 years, compared with 1.7% among the 180 patients who did have a preoperative MRI (P = .002). However, Dr. Rosenkranz said these differences should be interpreted with caution.
“We may look at these data and think we should consider preoperative breast MRI in patients who do have known multiple ipsilateral breast cancer, although I think this cohort was certainly much too small to draw definitive conclusions, and this was not a planned secondary endpoint of the trial,” she said during her presentation.
Most prefer breast conservation, when possible
Overall, the findings are important considering the array of known benefits of breast conservation over mastectomy, Dr. Rosenkranz concluded.
“The reason this is so important is that we know that patients who undergo breast conservation report improved quality of life, self-esteem, and body image, and therefore it’s incumbent on us as surgeons to expand the indications for breast conservation where we can,” she told the audience.
Speaking with this news organization, she added that the decision-making around breast conservation versus mastectomy can be complicated, and some women do opt for mastectomy because of a variety of factors; therefore, “tailoring therapy to the individual goals and priorities in addition to the disease characteristics is critical.”
That said, she added that “the majority of patients who are eligible for breast conservation do prefer this option.”
Dr. Rosenkranz and Dr. Cody have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
BOSTON – , as new data show a low risk of recurrence at 5 years when they are treated with breast-conserving therapy and radiation.
“[The study] proves the oncologic safety of breast conservation in women with two or three sites of disease, making this a very reasonable option for (previously reluctant) surgeons to present to patients,” first author Kari Rosenkranz, MD, an associate professor at Dartmouth Health in Norwich, Vt., said in an interview.
The findings were presented here at the International Conference on Surgical Cancer Care (SSO 2023), and were published online in the Journal of Clinical Oncology.
Commenting on the study, Hiram S. Cody III, MD, an attending surgeon and professor of surgery at Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, in New York, said the findings provide valuable new evidence on the issue.
“This is an important study confirming that breast conservation is feasible and safe for women with multiple ipsilateral breast cancers, with excellent results comparable to those for women with unifocal (single site) disease,” he said in an interview.
Although there have been as many as seven previous randomized trials that have shown identical outcomes in survival and local control of disease with breast-conserving therapy versus mastectomy, all those studies excluded patients with more than one site of disease.
At present, many surgeons and guidelines continue to recommend mastectomy for women with multiple-site tumors, based on older data that showed higher recurrence rates.
That is why the new study is so important, Dr. Cody explained. “Here, we see in a prospective trial that breast-conserving therapy is feasible for those with more than one site of disease as well, with high survival and very low rates of local recurrence,” he emphasized.
Dr. Cody noted that “the ideal candidate would be a woman with relatively small tumor size and a breast large enough that the multiple excisions could be performed with a good cosmetic result.”
“We have followed this approach for some time and hope that with the publication of these results more surgeons will recommend this approach for suitable patients,” he said.
The new results were also highlighted in a press release from Mayo Clinic highlighting the Journal of Clinical Oncology publication. Lead author of the article, surgical oncologist Judy Boughey, MD, from the Mayo Clinic in Rochester, Minn., commented: “I am excited about these findings because it will empower patients and the multidisciplinary care teams caring for patients to be thinking about this option for women who may want to preserve their breast.”
This study showed the rate of cancer local recurrence was 3.1%, she noted. This is an excellent outcome and is similar to the local recurrence rate for patients with a single tumor in a breast who had breast-conserving therapy, Dr. Boughey said.
Historically, women with multiple tumors in one breast have been advised to have a mastectomy. Now, patients can be offered a less invasive option with faster recovery, resulting in better patient satisfaction and cosmetic outcomes, she added.
Study details
This study, known as the ACOSOG (Alliance) Z11102 trial, was a phase 2 trial conducted in 204 patients enrolled between 2012 and 2016 who had two or three sites of biopsy-proven breast cancer (each site less rhan 5 cm in size, with cN0 or cN1 disease).
These patients were a median age of 61 years, and 83.5% were ER-positive/HER2-negative, 11.5% were HER2-positive, 5.0% were ER-negative/HER2-negative, and 77.5% were node-negative.
All patients were treated with breast conservation surgery, including lumpectomy resected to negative margins, followed by whole breast radiation with a cavity boost to all lumpectomy beds.
With a median follow-up of 66.4 months, six patients developed local recurrence, with five of the recurrences occurring in the ipsilateral breast and one in the chest wall.
For the primary endpoint, the six recurrences represented an estimated cumulative incidence of local recurrence of 3.1% (95% CI, 1.3-6.4), well below the cutoff of 8% that was determined to be the acceptable 5-year local recurrence rate based on historic recurrence rates for unifocal disease, Dr. Rosenkranz explained.
There were no cases of synchronous local and distant recurrences, six contralateral breast cancers, and three new primary nonbreast cancers. Eight patients died, including one related to breast cancer.
There were no significant associations between risk of local recurrence and factors including patient age, number of sites of preoperative biopsy-proven breast cancer, HER2 status, and pathologic T and N category.
In terms of secondary endpoints, 14 patients (7.1%) converted to mastectomy because of positive margins, while 67.6% achieved margin-negative excision in a single operation.
Regarding cosmesis, 70.6% of patients reported good or excellent cosmetic outcomes at 2 years.
In terms of adherence, the whole breast radiation therapy protocol was feasible in most patients.
Of note, among patients without a breast preoperative MRI, the 5-year rate of local recurrence was significantly higher, at 22.6% (n = 14) at 5 years, compared with 1.7% among the 180 patients who did have a preoperative MRI (P = .002). However, Dr. Rosenkranz said these differences should be interpreted with caution.
“We may look at these data and think we should consider preoperative breast MRI in patients who do have known multiple ipsilateral breast cancer, although I think this cohort was certainly much too small to draw definitive conclusions, and this was not a planned secondary endpoint of the trial,” she said during her presentation.
Most prefer breast conservation, when possible
Overall, the findings are important considering the array of known benefits of breast conservation over mastectomy, Dr. Rosenkranz concluded.
“The reason this is so important is that we know that patients who undergo breast conservation report improved quality of life, self-esteem, and body image, and therefore it’s incumbent on us as surgeons to expand the indications for breast conservation where we can,” she told the audience.
Speaking with this news organization, she added that the decision-making around breast conservation versus mastectomy can be complicated, and some women do opt for mastectomy because of a variety of factors; therefore, “tailoring therapy to the individual goals and priorities in addition to the disease characteristics is critical.”
That said, she added that “the majority of patients who are eligible for breast conservation do prefer this option.”
Dr. Rosenkranz and Dr. Cody have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM SSO 2023
Strong support for CBT as first-line treatment for insomnia in seniors
NEW ORLEANS –
“The lack of awareness among clinicians who take care of older adults that CBT for insomnia (CBT-I) is an effective treatment for insomnia is an issue,” Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry, Creighton University, Omaha, Neb., told this news organization.
Dr. Tampi was among the speakers during a session as part of the American Association for Geriatric Psychiatry annual meeting addressing the complex challenges of treating insomnia in older patients, who tend to have higher rates of insomnia than their younger counterparts.
The prevalence of insomnia in older adults is estimated to be 20%-40%, and medication is frequently the first treatment choice, a less than ideal approach, said Dr. Tampi.
“Prescribing sedatives and hypnotics, which can cause severe adverse effects, without a thorough assessment that includes comorbidities that may be causing the insomnia” is among the biggest mistakes clinicians make in the treatment of insomnia in older patients, Dr. Tampi said in an interview.
“It’s our duty as providers to first take a good assessment, talk about polymorbidity, and try to address those conditions, and judiciously use medications in conjunction with at least components of CBT-I,” he said.
Long-term safety, efficacy unclear
About one-third of older adults take at least one form of pharmacological treatment for insomnia symptoms, said Ebony Dix, MD, assistant professor of psychiatry at Yale University, New Haven, Conn., in a separate talk during the session. This, despite the low-risk profile of CBT and recommendations from various medical societies that CBT should be tried first.
Dr. Dix noted that medications approved for insomnia by the U.S. Food and Drug Administration, including melatonin receptor agonists, heterocyclics, and dual orexin receptor antagonists (DORAs), can play an important role in the short-term management of insomnia, but their long-term effects are unknown.
“Pharmacotherapeutic agents may be effective in the short term, but there is a lack of sufficient, statistically significant data to support the long-term safety and efficacy of any [sleep] medication, especially in aging adults, due to the impact of hypnotic drugs on sleep architecture, the impact of aging on pharmacokinetics, as well as polypharmacy and drug-to-drug interactions,” Dr. Dix said. She noted that clinical trials of insomnia drugs rarely include geriatric patients.
The American Academy of Sleep Medicine recommends CBT-I as first-line treatment for insomnia, with the key benefit being its exemplary safety profile, said Shilpa Srinivasan, MD, a professor of clinical psychiatry at the University of South Carolina, Columbia, who also presented during the session.
“The biggest [attribute] of CBT-I management strategies is the low risk of side effects,” she said. “How many medications can we say that about?”
The CBT-I intervention includes a focus on key components of lifestyle and mental health issues to improve sleep. These include the following:
- Strictly restricting sleep hours for bedtime and arising (with napping discouraged).
- Control of stimulus to disrupt falling asleep.
- Cognitive therapy to identify and replace maladaptive beliefs.
- Control of sleep hygiene for optimal sleep.
- Relaxation training.
Keys to success
Dr. Srinivasan noted one recent study of CBT-I among patients aged 60 and older with insomnia and depression. The 156 participants randomized to receive weekly 120-minute CBT-I sessions over 2 months were significantly less likely to develop new or recurrent major depression versus their counterparts randomized to receive sleep education (hazard ratio, 0.51; P = .02).
However, CBT-I is more labor intensive than medication and requires provider training and motivation, and commitment on the part of the patient, to be successful.
“We really need to ensure that even when patients are receiving pharmacologic interventions for insomnia that we provide psychoeducation. At the end of the day, some of these nonpharmacologic components can make or break the success of pharmacotherapy,” said Dr. Srinivasan.
Whether using CBT-I alone or in combination with pharmacotherapy, the intervention does not necessarily have to include all components to be beneficial, she said.
“I think one of the challenges in incorporating CBT-I is the misconception that it is an all-or-nothing approach wherein every modality must be utilized,” she said. “While multicomponent CBT-I has been shown to be effective, the individual components can be incorporated into patient encounters in a stepped approach.”
Informing patients that they have options other than medications and involving them in decision-making is key, she added.
“In the case of insomnia, this is particularly relevant because of the physical and emotional distress that it causes,” Dr. Srinivasan said. “Patients often seek over-the-counter medications or other nonprescribed agents to try to obtain relief even before seeking treatment in a health care setting. There is less awareness about evidence-based and effective nonpharmacologic treatments such as CBT-I.”
Dr. Tampi, Dr. Dix, and Dr. Srinivasan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
“The lack of awareness among clinicians who take care of older adults that CBT for insomnia (CBT-I) is an effective treatment for insomnia is an issue,” Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry, Creighton University, Omaha, Neb., told this news organization.
Dr. Tampi was among the speakers during a session as part of the American Association for Geriatric Psychiatry annual meeting addressing the complex challenges of treating insomnia in older patients, who tend to have higher rates of insomnia than their younger counterparts.
The prevalence of insomnia in older adults is estimated to be 20%-40%, and medication is frequently the first treatment choice, a less than ideal approach, said Dr. Tampi.
“Prescribing sedatives and hypnotics, which can cause severe adverse effects, without a thorough assessment that includes comorbidities that may be causing the insomnia” is among the biggest mistakes clinicians make in the treatment of insomnia in older patients, Dr. Tampi said in an interview.
“It’s our duty as providers to first take a good assessment, talk about polymorbidity, and try to address those conditions, and judiciously use medications in conjunction with at least components of CBT-I,” he said.
Long-term safety, efficacy unclear
About one-third of older adults take at least one form of pharmacological treatment for insomnia symptoms, said Ebony Dix, MD, assistant professor of psychiatry at Yale University, New Haven, Conn., in a separate talk during the session. This, despite the low-risk profile of CBT and recommendations from various medical societies that CBT should be tried first.
Dr. Dix noted that medications approved for insomnia by the U.S. Food and Drug Administration, including melatonin receptor agonists, heterocyclics, and dual orexin receptor antagonists (DORAs), can play an important role in the short-term management of insomnia, but their long-term effects are unknown.
“Pharmacotherapeutic agents may be effective in the short term, but there is a lack of sufficient, statistically significant data to support the long-term safety and efficacy of any [sleep] medication, especially in aging adults, due to the impact of hypnotic drugs on sleep architecture, the impact of aging on pharmacokinetics, as well as polypharmacy and drug-to-drug interactions,” Dr. Dix said. She noted that clinical trials of insomnia drugs rarely include geriatric patients.
The American Academy of Sleep Medicine recommends CBT-I as first-line treatment for insomnia, with the key benefit being its exemplary safety profile, said Shilpa Srinivasan, MD, a professor of clinical psychiatry at the University of South Carolina, Columbia, who also presented during the session.
“The biggest [attribute] of CBT-I management strategies is the low risk of side effects,” she said. “How many medications can we say that about?”
The CBT-I intervention includes a focus on key components of lifestyle and mental health issues to improve sleep. These include the following:
- Strictly restricting sleep hours for bedtime and arising (with napping discouraged).
- Control of stimulus to disrupt falling asleep.
- Cognitive therapy to identify and replace maladaptive beliefs.
- Control of sleep hygiene for optimal sleep.
- Relaxation training.
Keys to success
Dr. Srinivasan noted one recent study of CBT-I among patients aged 60 and older with insomnia and depression. The 156 participants randomized to receive weekly 120-minute CBT-I sessions over 2 months were significantly less likely to develop new or recurrent major depression versus their counterparts randomized to receive sleep education (hazard ratio, 0.51; P = .02).
However, CBT-I is more labor intensive than medication and requires provider training and motivation, and commitment on the part of the patient, to be successful.
“We really need to ensure that even when patients are receiving pharmacologic interventions for insomnia that we provide psychoeducation. At the end of the day, some of these nonpharmacologic components can make or break the success of pharmacotherapy,” said Dr. Srinivasan.
Whether using CBT-I alone or in combination with pharmacotherapy, the intervention does not necessarily have to include all components to be beneficial, she said.
“I think one of the challenges in incorporating CBT-I is the misconception that it is an all-or-nothing approach wherein every modality must be utilized,” she said. “While multicomponent CBT-I has been shown to be effective, the individual components can be incorporated into patient encounters in a stepped approach.”
Informing patients that they have options other than medications and involving them in decision-making is key, she added.
“In the case of insomnia, this is particularly relevant because of the physical and emotional distress that it causes,” Dr. Srinivasan said. “Patients often seek over-the-counter medications or other nonprescribed agents to try to obtain relief even before seeking treatment in a health care setting. There is less awareness about evidence-based and effective nonpharmacologic treatments such as CBT-I.”
Dr. Tampi, Dr. Dix, and Dr. Srinivasan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
“The lack of awareness among clinicians who take care of older adults that CBT for insomnia (CBT-I) is an effective treatment for insomnia is an issue,” Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry, Creighton University, Omaha, Neb., told this news organization.
Dr. Tampi was among the speakers during a session as part of the American Association for Geriatric Psychiatry annual meeting addressing the complex challenges of treating insomnia in older patients, who tend to have higher rates of insomnia than their younger counterparts.
The prevalence of insomnia in older adults is estimated to be 20%-40%, and medication is frequently the first treatment choice, a less than ideal approach, said Dr. Tampi.
“Prescribing sedatives and hypnotics, which can cause severe adverse effects, without a thorough assessment that includes comorbidities that may be causing the insomnia” is among the biggest mistakes clinicians make in the treatment of insomnia in older patients, Dr. Tampi said in an interview.
“It’s our duty as providers to first take a good assessment, talk about polymorbidity, and try to address those conditions, and judiciously use medications in conjunction with at least components of CBT-I,” he said.
Long-term safety, efficacy unclear
About one-third of older adults take at least one form of pharmacological treatment for insomnia symptoms, said Ebony Dix, MD, assistant professor of psychiatry at Yale University, New Haven, Conn., in a separate talk during the session. This, despite the low-risk profile of CBT and recommendations from various medical societies that CBT should be tried first.
Dr. Dix noted that medications approved for insomnia by the U.S. Food and Drug Administration, including melatonin receptor agonists, heterocyclics, and dual orexin receptor antagonists (DORAs), can play an important role in the short-term management of insomnia, but their long-term effects are unknown.
“Pharmacotherapeutic agents may be effective in the short term, but there is a lack of sufficient, statistically significant data to support the long-term safety and efficacy of any [sleep] medication, especially in aging adults, due to the impact of hypnotic drugs on sleep architecture, the impact of aging on pharmacokinetics, as well as polypharmacy and drug-to-drug interactions,” Dr. Dix said. She noted that clinical trials of insomnia drugs rarely include geriatric patients.
The American Academy of Sleep Medicine recommends CBT-I as first-line treatment for insomnia, with the key benefit being its exemplary safety profile, said Shilpa Srinivasan, MD, a professor of clinical psychiatry at the University of South Carolina, Columbia, who also presented during the session.
“The biggest [attribute] of CBT-I management strategies is the low risk of side effects,” she said. “How many medications can we say that about?”
The CBT-I intervention includes a focus on key components of lifestyle and mental health issues to improve sleep. These include the following:
- Strictly restricting sleep hours for bedtime and arising (with napping discouraged).
- Control of stimulus to disrupt falling asleep.
- Cognitive therapy to identify and replace maladaptive beliefs.
- Control of sleep hygiene for optimal sleep.
- Relaxation training.
Keys to success
Dr. Srinivasan noted one recent study of CBT-I among patients aged 60 and older with insomnia and depression. The 156 participants randomized to receive weekly 120-minute CBT-I sessions over 2 months were significantly less likely to develop new or recurrent major depression versus their counterparts randomized to receive sleep education (hazard ratio, 0.51; P = .02).
However, CBT-I is more labor intensive than medication and requires provider training and motivation, and commitment on the part of the patient, to be successful.
“We really need to ensure that even when patients are receiving pharmacologic interventions for insomnia that we provide psychoeducation. At the end of the day, some of these nonpharmacologic components can make or break the success of pharmacotherapy,” said Dr. Srinivasan.
Whether using CBT-I alone or in combination with pharmacotherapy, the intervention does not necessarily have to include all components to be beneficial, she said.
“I think one of the challenges in incorporating CBT-I is the misconception that it is an all-or-nothing approach wherein every modality must be utilized,” she said. “While multicomponent CBT-I has been shown to be effective, the individual components can be incorporated into patient encounters in a stepped approach.”
Informing patients that they have options other than medications and involving them in decision-making is key, she added.
“In the case of insomnia, this is particularly relevant because of the physical and emotional distress that it causes,” Dr. Srinivasan said. “Patients often seek over-the-counter medications or other nonprescribed agents to try to obtain relief even before seeking treatment in a health care setting. There is less awareness about evidence-based and effective nonpharmacologic treatments such as CBT-I.”
Dr. Tampi, Dr. Dix, and Dr. Srinivasan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT AAGP 2023
New data on IV ketamine for resistant depression in the elderly
NEW ORLEANS –
“These were patients with depression who had not responded even to intensive therapies or procedures, and we found that after a 6-week ketamine infusion regimen, there was no difference in the response to the treatment between the treatment-resistant geriatric and nongeriatric patients,” study investigator Jonathan Kim, of Emory University, Atlanta, the first author of one of two studies presented as part of the American Association for Geriatric Psychiatry annual meeting, said in an interview.
The findings are important because research on the effects of IV ketamine have not been well documented in geriatric patients, who have high rates of depression and TRD.
“There is a lack of data on IV ketamine in older adults with treatment-resistant depression, and there are some safety and tolerability concerns which may lead some older adults and their clinicians to be reluctant to pursue IV ketamine treatment,” study coinvestigator Hanadi Ajam Oughli, MD, a health sciences assistant clinical professor in the department of psychiatry and biobehavioral sciences, University of California, Los Angeles, told this news organization.
Nasal vs. IV administration
Ketamine has traditionally been used as an anesthetic that blocks N-methyl-D-aspartate (NMDA) glutamate receptors, Dr. Oughli and colleagues note.
In the treatment of TRD, an infusion of 0.5 mg/kg is typically administered over 40 minutes, producing a rapid antidepressant response. Recent research shows the drug reduces suicidality and improves mood and quality of life.
A more recent intranasal formulation of ketamine, esketamine, was approved by the U.S. Food and Drug Administration for TRD in 2019, and some experts questioned its path to approval. In addition, the drug’s high cost and poor bioavailability in comparison with IV ketamine remains an issue, said Dr. Oughli.
In the previous TRANSFORM-3 study, a placebo-controlled randomized trial, there was no difference between esketamine, used in conjunction with an antidepressant, and placebo for geriatric patients.
To better understand the effects of IV ketamine in this patient population, Mr. Kim’s team conducted a retrospective chart review of 91 older patients with TRD who received IV ketamine treatment between October 2016 and August 2022.
Patients were divided into two groups – those older than 60 years (n = 36; 44% women; mean age, 68.86) and those younger than 60 (n = 55; 49% women; mean age, 41.05). Participants in each age group received six ketamine infusions over 6 weeks.
Results showed that with regard to depression severity, as assessed using Beck Depression Inventory (BDI-II) scores, 27.8% of patients in the geriatric group had a 50% or greater improvement, vs. 25.4% of those younger than 60.
The average BDI-II scores represented a significant improvement for both groups (P < .01), and the difference in scores between the groups was not statistically significant (P = .973).
“It is important to note that our study was conducted in a real-world clinical setting with a treatment-resistant population; other clinical studies may not have such sick patients in their trials. Additional studies are therefore warranted to establish further treatment guidelines in this area,” Mr. Kim said.
Open-label trial results
In the second study, Dr. Oughli and colleagues evaluated additional key outcomes in geriatric patients treated with IV ketamine as part of a larger open-label late-life trial on TRD.
The secondary analysis of the trial focused on 23 patients (mean age, 71.5 years) who had been initially treated with twice-a-week IV ketamine for 4 weeks.
After the first 4 weeks, patients who had experienced a partial response received an additional 4 weeks of once-weekly IV ketamine.
Overall, 48% of participants achieved a response, and 24% achieved remission of depressive symptoms following the first 4 weeks of twice-weekly treatment. This effect was maintained during the continuation phase of the study.
These findings are consistent with research in younger adults and demonstrate that twice-weekly infusions yield a more sustained antidepressant response than once-weekly infusions, the authors note.
The analysis also showed important increases in psychological well-being scores on the Scale for Suicidal Ideation, improved sleep quality as measured by the Pittsburgh Sleep Quality Index, and overall psychological well-being as shown on the NIH Toolbox Positive Affect on happiness/contentment and the NIH Toolbox General Life Satisfaction scales.
In a previous analysis, published in The American Journal of Geriatric Psychiatry, the researchers also evaluated cognitive function using the NIH Cognitive Battery, which showed that geriatric patients with TRD had significant improvements in a composite of executive functioning and fluid cognition during the 4-week acute treatment period of twice-weekly IV ketamine infusions (Cohen’s d = 0.61) and that those improvements were sustained in the continuation phase of once-weekly infusions for 4 more weeks.
Those results are consistent with ketamine’s known potential procognitive effects in TRD, due to a putative antidepressant mechanism that rescues prefrontal circuit dysfunction through synaptogenesis, the researchers note.
Dr. Oughli said that in both analyses, patients tolerated ketamine well, and there were no serious adverse events.
“Adverse events, including hypertension, dissociated effects, and cravings, were rare and did not prevent the continued use of IV ketamine by older adults. We were able to use clonidine to help manage blood pressure changes seen during the infusions,” she noted.
“These findings are very promising and will need to be confirmed and extended in a larger randomized controlled trial.”
Unsettling for some older patients
George T. Grossberg, MD, director, geriatric psychiatry, Saint Louis University, noted that in his experience, IV ketamine treatment can be unsettling for some older geriatric patients, such as those in their 80s.
“Particularly with some of my older patients, the kind of psychotomimetic properties of ketamine and the out-of-body experiences [with the initial treatment] can be frightening,” he said. “They may be willing to try, but I’ve had more than one patient quit after one treatment because they became so frightened.”
However, the dire nature of TRD and failure to respond to multiple medications and combinations and other strategies may prompt patients to try ketamine as a measure with at least some potential, he noted.
“But there is a high bar for acceptance, especially on the part of older adults and their families, more than for younger people,” he said.
The investigators have disclosed no relevant financial relationships. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
“These were patients with depression who had not responded even to intensive therapies or procedures, and we found that after a 6-week ketamine infusion regimen, there was no difference in the response to the treatment between the treatment-resistant geriatric and nongeriatric patients,” study investigator Jonathan Kim, of Emory University, Atlanta, the first author of one of two studies presented as part of the American Association for Geriatric Psychiatry annual meeting, said in an interview.
The findings are important because research on the effects of IV ketamine have not been well documented in geriatric patients, who have high rates of depression and TRD.
“There is a lack of data on IV ketamine in older adults with treatment-resistant depression, and there are some safety and tolerability concerns which may lead some older adults and their clinicians to be reluctant to pursue IV ketamine treatment,” study coinvestigator Hanadi Ajam Oughli, MD, a health sciences assistant clinical professor in the department of psychiatry and biobehavioral sciences, University of California, Los Angeles, told this news organization.
Nasal vs. IV administration
Ketamine has traditionally been used as an anesthetic that blocks N-methyl-D-aspartate (NMDA) glutamate receptors, Dr. Oughli and colleagues note.
In the treatment of TRD, an infusion of 0.5 mg/kg is typically administered over 40 minutes, producing a rapid antidepressant response. Recent research shows the drug reduces suicidality and improves mood and quality of life.
A more recent intranasal formulation of ketamine, esketamine, was approved by the U.S. Food and Drug Administration for TRD in 2019, and some experts questioned its path to approval. In addition, the drug’s high cost and poor bioavailability in comparison with IV ketamine remains an issue, said Dr. Oughli.
In the previous TRANSFORM-3 study, a placebo-controlled randomized trial, there was no difference between esketamine, used in conjunction with an antidepressant, and placebo for geriatric patients.
To better understand the effects of IV ketamine in this patient population, Mr. Kim’s team conducted a retrospective chart review of 91 older patients with TRD who received IV ketamine treatment between October 2016 and August 2022.
Patients were divided into two groups – those older than 60 years (n = 36; 44% women; mean age, 68.86) and those younger than 60 (n = 55; 49% women; mean age, 41.05). Participants in each age group received six ketamine infusions over 6 weeks.
Results showed that with regard to depression severity, as assessed using Beck Depression Inventory (BDI-II) scores, 27.8% of patients in the geriatric group had a 50% or greater improvement, vs. 25.4% of those younger than 60.
The average BDI-II scores represented a significant improvement for both groups (P < .01), and the difference in scores between the groups was not statistically significant (P = .973).
“It is important to note that our study was conducted in a real-world clinical setting with a treatment-resistant population; other clinical studies may not have such sick patients in their trials. Additional studies are therefore warranted to establish further treatment guidelines in this area,” Mr. Kim said.
Open-label trial results
In the second study, Dr. Oughli and colleagues evaluated additional key outcomes in geriatric patients treated with IV ketamine as part of a larger open-label late-life trial on TRD.
The secondary analysis of the trial focused on 23 patients (mean age, 71.5 years) who had been initially treated with twice-a-week IV ketamine for 4 weeks.
After the first 4 weeks, patients who had experienced a partial response received an additional 4 weeks of once-weekly IV ketamine.
Overall, 48% of participants achieved a response, and 24% achieved remission of depressive symptoms following the first 4 weeks of twice-weekly treatment. This effect was maintained during the continuation phase of the study.
These findings are consistent with research in younger adults and demonstrate that twice-weekly infusions yield a more sustained antidepressant response than once-weekly infusions, the authors note.
The analysis also showed important increases in psychological well-being scores on the Scale for Suicidal Ideation, improved sleep quality as measured by the Pittsburgh Sleep Quality Index, and overall psychological well-being as shown on the NIH Toolbox Positive Affect on happiness/contentment and the NIH Toolbox General Life Satisfaction scales.
In a previous analysis, published in The American Journal of Geriatric Psychiatry, the researchers also evaluated cognitive function using the NIH Cognitive Battery, which showed that geriatric patients with TRD had significant improvements in a composite of executive functioning and fluid cognition during the 4-week acute treatment period of twice-weekly IV ketamine infusions (Cohen’s d = 0.61) and that those improvements were sustained in the continuation phase of once-weekly infusions for 4 more weeks.
Those results are consistent with ketamine’s known potential procognitive effects in TRD, due to a putative antidepressant mechanism that rescues prefrontal circuit dysfunction through synaptogenesis, the researchers note.
Dr. Oughli said that in both analyses, patients tolerated ketamine well, and there were no serious adverse events.
“Adverse events, including hypertension, dissociated effects, and cravings, were rare and did not prevent the continued use of IV ketamine by older adults. We were able to use clonidine to help manage blood pressure changes seen during the infusions,” she noted.
“These findings are very promising and will need to be confirmed and extended in a larger randomized controlled trial.”
Unsettling for some older patients
George T. Grossberg, MD, director, geriatric psychiatry, Saint Louis University, noted that in his experience, IV ketamine treatment can be unsettling for some older geriatric patients, such as those in their 80s.
“Particularly with some of my older patients, the kind of psychotomimetic properties of ketamine and the out-of-body experiences [with the initial treatment] can be frightening,” he said. “They may be willing to try, but I’ve had more than one patient quit after one treatment because they became so frightened.”
However, the dire nature of TRD and failure to respond to multiple medications and combinations and other strategies may prompt patients to try ketamine as a measure with at least some potential, he noted.
“But there is a high bar for acceptance, especially on the part of older adults and their families, more than for younger people,” he said.
The investigators have disclosed no relevant financial relationships. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
“These were patients with depression who had not responded even to intensive therapies or procedures, and we found that after a 6-week ketamine infusion regimen, there was no difference in the response to the treatment between the treatment-resistant geriatric and nongeriatric patients,” study investigator Jonathan Kim, of Emory University, Atlanta, the first author of one of two studies presented as part of the American Association for Geriatric Psychiatry annual meeting, said in an interview.
The findings are important because research on the effects of IV ketamine have not been well documented in geriatric patients, who have high rates of depression and TRD.
“There is a lack of data on IV ketamine in older adults with treatment-resistant depression, and there are some safety and tolerability concerns which may lead some older adults and their clinicians to be reluctant to pursue IV ketamine treatment,” study coinvestigator Hanadi Ajam Oughli, MD, a health sciences assistant clinical professor in the department of psychiatry and biobehavioral sciences, University of California, Los Angeles, told this news organization.
Nasal vs. IV administration
Ketamine has traditionally been used as an anesthetic that blocks N-methyl-D-aspartate (NMDA) glutamate receptors, Dr. Oughli and colleagues note.
In the treatment of TRD, an infusion of 0.5 mg/kg is typically administered over 40 minutes, producing a rapid antidepressant response. Recent research shows the drug reduces suicidality and improves mood and quality of life.
A more recent intranasal formulation of ketamine, esketamine, was approved by the U.S. Food and Drug Administration for TRD in 2019, and some experts questioned its path to approval. In addition, the drug’s high cost and poor bioavailability in comparison with IV ketamine remains an issue, said Dr. Oughli.
In the previous TRANSFORM-3 study, a placebo-controlled randomized trial, there was no difference between esketamine, used in conjunction with an antidepressant, and placebo for geriatric patients.
To better understand the effects of IV ketamine in this patient population, Mr. Kim’s team conducted a retrospective chart review of 91 older patients with TRD who received IV ketamine treatment between October 2016 and August 2022.
Patients were divided into two groups – those older than 60 years (n = 36; 44% women; mean age, 68.86) and those younger than 60 (n = 55; 49% women; mean age, 41.05). Participants in each age group received six ketamine infusions over 6 weeks.
Results showed that with regard to depression severity, as assessed using Beck Depression Inventory (BDI-II) scores, 27.8% of patients in the geriatric group had a 50% or greater improvement, vs. 25.4% of those younger than 60.
The average BDI-II scores represented a significant improvement for both groups (P < .01), and the difference in scores between the groups was not statistically significant (P = .973).
“It is important to note that our study was conducted in a real-world clinical setting with a treatment-resistant population; other clinical studies may not have such sick patients in their trials. Additional studies are therefore warranted to establish further treatment guidelines in this area,” Mr. Kim said.
Open-label trial results
In the second study, Dr. Oughli and colleagues evaluated additional key outcomes in geriatric patients treated with IV ketamine as part of a larger open-label late-life trial on TRD.
The secondary analysis of the trial focused on 23 patients (mean age, 71.5 years) who had been initially treated with twice-a-week IV ketamine for 4 weeks.
After the first 4 weeks, patients who had experienced a partial response received an additional 4 weeks of once-weekly IV ketamine.
Overall, 48% of participants achieved a response, and 24% achieved remission of depressive symptoms following the first 4 weeks of twice-weekly treatment. This effect was maintained during the continuation phase of the study.
These findings are consistent with research in younger adults and demonstrate that twice-weekly infusions yield a more sustained antidepressant response than once-weekly infusions, the authors note.
The analysis also showed important increases in psychological well-being scores on the Scale for Suicidal Ideation, improved sleep quality as measured by the Pittsburgh Sleep Quality Index, and overall psychological well-being as shown on the NIH Toolbox Positive Affect on happiness/contentment and the NIH Toolbox General Life Satisfaction scales.
In a previous analysis, published in The American Journal of Geriatric Psychiatry, the researchers also evaluated cognitive function using the NIH Cognitive Battery, which showed that geriatric patients with TRD had significant improvements in a composite of executive functioning and fluid cognition during the 4-week acute treatment period of twice-weekly IV ketamine infusions (Cohen’s d = 0.61) and that those improvements were sustained in the continuation phase of once-weekly infusions for 4 more weeks.
Those results are consistent with ketamine’s known potential procognitive effects in TRD, due to a putative antidepressant mechanism that rescues prefrontal circuit dysfunction through synaptogenesis, the researchers note.
Dr. Oughli said that in both analyses, patients tolerated ketamine well, and there were no serious adverse events.
“Adverse events, including hypertension, dissociated effects, and cravings, were rare and did not prevent the continued use of IV ketamine by older adults. We were able to use clonidine to help manage blood pressure changes seen during the infusions,” she noted.
“These findings are very promising and will need to be confirmed and extended in a larger randomized controlled trial.”
Unsettling for some older patients
George T. Grossberg, MD, director, geriatric psychiatry, Saint Louis University, noted that in his experience, IV ketamine treatment can be unsettling for some older geriatric patients, such as those in their 80s.
“Particularly with some of my older patients, the kind of psychotomimetic properties of ketamine and the out-of-body experiences [with the initial treatment] can be frightening,” he said. “They may be willing to try, but I’ve had more than one patient quit after one treatment because they became so frightened.”
However, the dire nature of TRD and failure to respond to multiple medications and combinations and other strategies may prompt patients to try ketamine as a measure with at least some potential, he noted.
“But there is a high bar for acceptance, especially on the part of older adults and their families, more than for younger people,” he said.
The investigators have disclosed no relevant financial relationships. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda.
A version of this article first appeared on Medscape.com.
AT AAGP 2023
Add-on antipsychotic beats switching meds in older adults with resistant depression
NEW ORLEANS –
“We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being – which means how positive and satisfied patients felt – and this is good news,” study investigator Eric J. Lenze, MD, of the department of psychiatry, Washington University, St. Louis, said in a press statement.
“However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people,” he added.
The findings were presented here as part of the American Association for Geriatric Psychiatry annual meeting, and published concurrently in the New England Journal of Medicine.
Need for safe treatment options
Treatment-resistant depression is common in older patients, but switching medications or adding other agents can be challenging. With higher rates of comorbidity and polypharmacy, treatment decisions in this patient population are more complex compared with those involving younger patients.
To compare the benefits of augmentation vs. drug-switching strategies, the researchers conducted a multicenter, two-step trial involving 619 patients with an average baseline age of 69 who had failed to respond to two courses of selective serotonin reuptake inhibitors (SSRIs).
Patients were randomly assigned to one of three groups. These included augmentation of existing antidepressant medication with either aripiprazole (n = 211) or the dopamine and norepinephrine–reuptake inhibitor bupropion (Wellbutrin, Zyban) (n = 206), or to taper off of their current antidepressant and switch to bupropion (n = 202).
After 10 weeks, patients’ psychological well-being was assessed via the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales. The researchers found patients in the aripiprazole and bupropion add-on groups improved by 4.83 points and 4.33 points, respectively. The bupropion switch group had a change of 2.04 points.
The difference between the aripiprazole augmentation group and the switch to bupropion group was significant (difference 2.79 points; P = .014). Other between-group differences were not significantly different.
Remission rates were similar in the aripiprazole and bupropion groups at 28.9% and 28.2%, respectively. The remission rate in the bupropion switch group was 19.3%.
The study results showed patients who received adjunctive bupropion had the highest fall rate at 0.55 falls per patient, vs. 0.33 falls per patient in the aripiprazole group, suggesting that among the three treatment options, adjunctive aripiprazole may be the best choice because of its superior efficacy and lower fall risk.
A total of 248 patients enrolled in the study showed no improvement and were further randomly assigned to receive adjunctive lithium (n = 127) or switch from current therapy to nortriptyline (n = 121).
Well-being scores in the lithium group improved by 3.17 points and 2.18 points in the nortriptyline group. Remission occurred in 18.9% of patients in the lithium group and 21.5% in the nortriptyline group. Fall rates were similar among the two groups.
Overall, “this large, randomized study demonstrated that adding aripiprazole was a superior option for older adults with treatment-resistant depression,” Dr. Lenze told this news organization.
“Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases,” he added.
Practice changing?
In an accompanying editorial, Gemma Lewis, PhD, and Glyn Lewis, PhD, division of psychiatry, University of College London, noted the findings “support aripiprazole augmentation as a strategy for treatment-resistant depression in older persons, largely because of the lower risk of falls than with bupropion augmentation.”
However, “in clinical practice, [it] would be important to tailor treatment in light of potential adverse effects and the preferences of the patient,” they added.
Akathisia, for instance, is a common side effect of aripiprazole, shown in one recent trial to affect 11% of the patients. In addition, weight gain, though typically lower than seen with other antipsychotics, is a consideration with aripiprazole.
With respect to fall risk, they noted that bupropion was largely used in relatively high doses of 300 mg and 450 mg, despite some recent research showing little clinical benefit from increasing antidepressant doses above minimum recommendations.
“It is possible that smaller doses of bupropion than those used in the current trial would retain effectiveness while minimizing adverse effects such as falls,” the editorialists noted.
Commenting on the study, Jennifer R. Gatchel, MD, PhD, assistant psychiatrist at Massachusetts General Hospital/McLean Hospital and assistant professor of psychiatry at Harvard Medical School, Boston, said the findings have high clinical significance in the treatment of geriatric depression. 
“These results are of great impact for clinicians managing older adults with treatment-resistant depression. They provide some of the first evidence of safety and efficacy of augmentation with aripiprazole as a strategy in clinical management of older adults who fail to initially respond to treatment,” said Dr. Gatchel, who was not associated with this research.
“Of particular significance, efficacy here is based on patient-centered outcomes and psychological well-being as a primary effectiveness outcome, which could translate into strengthened physician-patient alliance.”
While adjunctive aripiprazole is not necessarily a first-line strategy when older adults fail to respond to antidepressants, there is a lack of data on the risks and benefits of any other antipsychotic medications, she noted.
“Thus, this is evidence that will impact clinical practice and hopefully contribute to reduced societal burden of depression in older adults and the morbidity and mortality associated with it,” Dr. Gatchel said.
The study received support from a Patient-Centered Outcomes Research Institute (PCORI) Award (TRD-1511-33321). Dr. Lenze received additional support from the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, as well as the Washington University Institute of Clinical and Translational Sciences grant (UL1TR002345) from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Gatchel reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
“We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being – which means how positive and satisfied patients felt – and this is good news,” study investigator Eric J. Lenze, MD, of the department of psychiatry, Washington University, St. Louis, said in a press statement.
“However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people,” he added.
The findings were presented here as part of the American Association for Geriatric Psychiatry annual meeting, and published concurrently in the New England Journal of Medicine.
Need for safe treatment options
Treatment-resistant depression is common in older patients, but switching medications or adding other agents can be challenging. With higher rates of comorbidity and polypharmacy, treatment decisions in this patient population are more complex compared with those involving younger patients.
To compare the benefits of augmentation vs. drug-switching strategies, the researchers conducted a multicenter, two-step trial involving 619 patients with an average baseline age of 69 who had failed to respond to two courses of selective serotonin reuptake inhibitors (SSRIs).
Patients were randomly assigned to one of three groups. These included augmentation of existing antidepressant medication with either aripiprazole (n = 211) or the dopamine and norepinephrine–reuptake inhibitor bupropion (Wellbutrin, Zyban) (n = 206), or to taper off of their current antidepressant and switch to bupropion (n = 202).
After 10 weeks, patients’ psychological well-being was assessed via the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales. The researchers found patients in the aripiprazole and bupropion add-on groups improved by 4.83 points and 4.33 points, respectively. The bupropion switch group had a change of 2.04 points.
The difference between the aripiprazole augmentation group and the switch to bupropion group was significant (difference 2.79 points; P = .014). Other between-group differences were not significantly different.
Remission rates were similar in the aripiprazole and bupropion groups at 28.9% and 28.2%, respectively. The remission rate in the bupropion switch group was 19.3%.
The study results showed patients who received adjunctive bupropion had the highest fall rate at 0.55 falls per patient, vs. 0.33 falls per patient in the aripiprazole group, suggesting that among the three treatment options, adjunctive aripiprazole may be the best choice because of its superior efficacy and lower fall risk.
A total of 248 patients enrolled in the study showed no improvement and were further randomly assigned to receive adjunctive lithium (n = 127) or switch from current therapy to nortriptyline (n = 121).
Well-being scores in the lithium group improved by 3.17 points and 2.18 points in the nortriptyline group. Remission occurred in 18.9% of patients in the lithium group and 21.5% in the nortriptyline group. Fall rates were similar among the two groups.
Overall, “this large, randomized study demonstrated that adding aripiprazole was a superior option for older adults with treatment-resistant depression,” Dr. Lenze told this news organization.
“Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases,” he added.
Practice changing?
In an accompanying editorial, Gemma Lewis, PhD, and Glyn Lewis, PhD, division of psychiatry, University of College London, noted the findings “support aripiprazole augmentation as a strategy for treatment-resistant depression in older persons, largely because of the lower risk of falls than with bupropion augmentation.”
However, “in clinical practice, [it] would be important to tailor treatment in light of potential adverse effects and the preferences of the patient,” they added.
Akathisia, for instance, is a common side effect of aripiprazole, shown in one recent trial to affect 11% of the patients. In addition, weight gain, though typically lower than seen with other antipsychotics, is a consideration with aripiprazole.
With respect to fall risk, they noted that bupropion was largely used in relatively high doses of 300 mg and 450 mg, despite some recent research showing little clinical benefit from increasing antidepressant doses above minimum recommendations.
“It is possible that smaller doses of bupropion than those used in the current trial would retain effectiveness while minimizing adverse effects such as falls,” the editorialists noted.
Commenting on the study, Jennifer R. Gatchel, MD, PhD, assistant psychiatrist at Massachusetts General Hospital/McLean Hospital and assistant professor of psychiatry at Harvard Medical School, Boston, said the findings have high clinical significance in the treatment of geriatric depression.
“These results are of great impact for clinicians managing older adults with treatment-resistant depression. They provide some of the first evidence of safety and efficacy of augmentation with aripiprazole as a strategy in clinical management of older adults who fail to initially respond to treatment,” said Dr. Gatchel, who was not associated with this research.
“Of particular significance, efficacy here is based on patient-centered outcomes and psychological well-being as a primary effectiveness outcome, which could translate into strengthened physician-patient alliance.”
While adjunctive aripiprazole is not necessarily a first-line strategy when older adults fail to respond to antidepressants, there is a lack of data on the risks and benefits of any other antipsychotic medications, she noted.
“Thus, this is evidence that will impact clinical practice and hopefully contribute to reduced societal burden of depression in older adults and the morbidity and mortality associated with it,” Dr. Gatchel said.
The study received support from a Patient-Centered Outcomes Research Institute (PCORI) Award (TRD-1511-33321). Dr. Lenze received additional support from the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, as well as the Washington University Institute of Clinical and Translational Sciences grant (UL1TR002345) from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Gatchel reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
“We found that adding aripiprazole led to higher rates of depression remission and greater improvements in psychological well-being – which means how positive and satisfied patients felt – and this is good news,” study investigator Eric J. Lenze, MD, of the department of psychiatry, Washington University, St. Louis, said in a press statement.
“However, even that approach helped only about 30% of people in the study with treatment-resistant depression, underscoring the need to find and develop more effective treatments that can help more people,” he added.
The findings were presented here as part of the American Association for Geriatric Psychiatry annual meeting, and published concurrently in the New England Journal of Medicine.
Need for safe treatment options
Treatment-resistant depression is common in older patients, but switching medications or adding other agents can be challenging. With higher rates of comorbidity and polypharmacy, treatment decisions in this patient population are more complex compared with those involving younger patients.
To compare the benefits of augmentation vs. drug-switching strategies, the researchers conducted a multicenter, two-step trial involving 619 patients with an average baseline age of 69 who had failed to respond to two courses of selective serotonin reuptake inhibitors (SSRIs).
Patients were randomly assigned to one of three groups. These included augmentation of existing antidepressant medication with either aripiprazole (n = 211) or the dopamine and norepinephrine–reuptake inhibitor bupropion (Wellbutrin, Zyban) (n = 206), or to taper off of their current antidepressant and switch to bupropion (n = 202).
After 10 weeks, patients’ psychological well-being was assessed via the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales. The researchers found patients in the aripiprazole and bupropion add-on groups improved by 4.83 points and 4.33 points, respectively. The bupropion switch group had a change of 2.04 points.
The difference between the aripiprazole augmentation group and the switch to bupropion group was significant (difference 2.79 points; P = .014). Other between-group differences were not significantly different.
Remission rates were similar in the aripiprazole and bupropion groups at 28.9% and 28.2%, respectively. The remission rate in the bupropion switch group was 19.3%.
The study results showed patients who received adjunctive bupropion had the highest fall rate at 0.55 falls per patient, vs. 0.33 falls per patient in the aripiprazole group, suggesting that among the three treatment options, adjunctive aripiprazole may be the best choice because of its superior efficacy and lower fall risk.
A total of 248 patients enrolled in the study showed no improvement and were further randomly assigned to receive adjunctive lithium (n = 127) or switch from current therapy to nortriptyline (n = 121).
Well-being scores in the lithium group improved by 3.17 points and 2.18 points in the nortriptyline group. Remission occurred in 18.9% of patients in the lithium group and 21.5% in the nortriptyline group. Fall rates were similar among the two groups.
Overall, “this large, randomized study demonstrated that adding aripiprazole was a superior option for older adults with treatment-resistant depression,” Dr. Lenze told this news organization.
“Since neither lithium nor nortriptyline were promising against treatment-resistant depression in older adults, those medications are unlikely to be helpful in most cases,” he added.
Practice changing?
In an accompanying editorial, Gemma Lewis, PhD, and Glyn Lewis, PhD, division of psychiatry, University of College London, noted the findings “support aripiprazole augmentation as a strategy for treatment-resistant depression in older persons, largely because of the lower risk of falls than with bupropion augmentation.”
However, “in clinical practice, [it] would be important to tailor treatment in light of potential adverse effects and the preferences of the patient,” they added.
Akathisia, for instance, is a common side effect of aripiprazole, shown in one recent trial to affect 11% of the patients. In addition, weight gain, though typically lower than seen with other antipsychotics, is a consideration with aripiprazole.
With respect to fall risk, they noted that bupropion was largely used in relatively high doses of 300 mg and 450 mg, despite some recent research showing little clinical benefit from increasing antidepressant doses above minimum recommendations.
“It is possible that smaller doses of bupropion than those used in the current trial would retain effectiveness while minimizing adverse effects such as falls,” the editorialists noted.
Commenting on the study, Jennifer R. Gatchel, MD, PhD, assistant psychiatrist at Massachusetts General Hospital/McLean Hospital and assistant professor of psychiatry at Harvard Medical School, Boston, said the findings have high clinical significance in the treatment of geriatric depression.
“These results are of great impact for clinicians managing older adults with treatment-resistant depression. They provide some of the first evidence of safety and efficacy of augmentation with aripiprazole as a strategy in clinical management of older adults who fail to initially respond to treatment,” said Dr. Gatchel, who was not associated with this research.
“Of particular significance, efficacy here is based on patient-centered outcomes and psychological well-being as a primary effectiveness outcome, which could translate into strengthened physician-patient alliance.”
While adjunctive aripiprazole is not necessarily a first-line strategy when older adults fail to respond to antidepressants, there is a lack of data on the risks and benefits of any other antipsychotic medications, she noted.
“Thus, this is evidence that will impact clinical practice and hopefully contribute to reduced societal burden of depression in older adults and the morbidity and mortality associated with it,” Dr. Gatchel said.
The study received support from a Patient-Centered Outcomes Research Institute (PCORI) Award (TRD-1511-33321). Dr. Lenze received additional support from the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, as well as the Washington University Institute of Clinical and Translational Sciences grant (UL1TR002345) from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Gatchel reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT AAGP 2023
Antipsychotic cuts Alzheimer’s-related agitation
results of a phase 3 study suggest.
“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.
Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.
Agitation common, distressing
With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.
Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.
The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.
To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.
Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.
Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).
The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).
Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).
Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).
Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).
“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.
Boxed warnings
Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.
Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.
One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.
This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.
Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.
“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.
In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.
In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.
“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.
Caution still warranted
Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”
He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.
Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”
Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”
“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said.
The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.
A version of this article first appeared on Medscape.com.
This article was updated 3/14/23.
results of a phase 3 study suggest.
“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.
Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.
Agitation common, distressing
With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.
Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.
The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.
To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.
Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.
Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).
The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).
Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).
Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).
Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).
“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.
Boxed warnings
Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.
Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.
One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.
This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.
Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.
“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.
In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.
In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.
“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.
Caution still warranted
Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”
He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.
Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”
Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”
“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said.
The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.
A version of this article first appeared on Medscape.com.
This article was updated 3/14/23.
results of a phase 3 study suggest.
“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.
Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.
Agitation common, distressing
With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.
Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.
The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.
To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.
Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.
Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).
The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).
Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).
Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).
Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).
“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.
Boxed warnings
Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.
Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.
One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.
This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.
Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.
“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.
In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.
In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.
“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.
Caution still warranted
Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”
He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.
Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”
Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”
“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said.
The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.
A version of this article first appeared on Medscape.com.
This article was updated 3/14/23.
AT AAGP 2023
Long-acting ART effective without viral suppression
as is typically required before initiation, results from two new studies suggest.
Meanwhile, a third study shows early promise of a long-acting ART regimen that could require injections only twice yearly.
“Instead of having the burden of taking a pill every day, patients with HIV can now have these choices of being able to forget about their treatment for up to 2 months at a time,” Moti N. Ramgopal, MD, first author of one of the three studies, said in a press conference at the Conference on Retroviruses and Opportunistic Infections. “My patients tell me that it’s game-changing for them.”
First head-to-head comparison
The injectable intramuscular combination of cabotegravir and rilpivirine, administered once every 1 or 2 months, is the first and only long-acting ART to be approved by the Food and Drug Administration for people with HIV. At the meeting, Dr. Ramgopal, from the Midway Immunology and Research Center in Fort Pierce, Fla., reported the results from the first head-to-head study comparing the regimen with the standard daily oral regimen of bictegravir/emtricitabine/tenofovir alafenamide (B/FTC/TAF).
For the phase 3b SOLAR trial, adults with HIV who were already virologically suppressed and treated with daily B/FTC/TAF were randomly assigned to remain on the oral regimen (n = 223) or switch to the long-acting injections every 2 months, either with an oral lead-in (n = 173) or without a lead-in (n = 274).
The results after 12 months showed noninferiority between the groups, with 90% of the long-acting ART group and 93% in the oral daily pill group maintaining viral suppression, defined as plasma HIV-1 RNA less than 50 copies/mL.
Two patients (0.4%) receiving the long-acting ART in a modified-intention to treat and 3 (0.6%) in the intention-to-treat populations had confirmed virologic failure, and rates of adverse events leading to withdrawal were 6% with the long-acting ART group versus 1% with the oral treatment group.
As many as 90% of subjects reported preferring the long-acting ART over their previous oral therapy at the end of the study, and those in the long-acting group also reported significantly greater improvements in quality of life on the HIV Treatment Satisfaction Questionnaire status version compared with the oral therapy group at the end of the study (P < .001).
Prior to the randomization, as many as 47% of patients on the oral regimen reported “always” or “often” having psychosocial challenges with the daily therapy, including worries of having their HIV status revealed and forgetting to take the medication.
“These data demonstrate that [the long-acting regimen] addresses important unmet needs for people with HIV who are virally suppressed on oral daily HIV therapy, while improving the quality of life,” said Dr. Ramgopal.
Suppression at onset not necessarily required
For all of its benefits, a key caveat of the cabotegravir and rilpivirine long-acting regimen is that it is approved only for patients who have already achieved viral suppression and are currently on oral ART, meaning some of the people most in need, including those with unstable housing, mental illness, or substance abuse disorders, may be excluded.
To evaluate the therapy’s efficacy among those patient types, Monica Gandhi, MD, MPH, professor of medicine and associate division chief at the University of California, San Francisco, enrolled 133 participants between June 2021 and November 2022 at the Ward 86 HIV Clinic, a safety-net clinic in San Francisco, to initiate long-acting ART. Participants included 57 patients (43%) with untreated or unsuppressed HIV, and 76 who were virally suppressed on oral ART.
Of the whole study group, 66% reported unstable housing, 8% reported experiencing homelessness, 38% reported having a mental illness, and 33% reported substance use.
Although all of the subjects (100%) who started with viral suppression remained suppressed over the study’s 26-week follow-up, the rate of viral suppression at the study’s end was nearly as high – 55 of 57 subjects (96.5%) – among those who started long-acting ART without having viral suppression.
Of note, the overall rate of study participants who did not achieve or maintain viral suppression (1.5%) was consistent with rates reported in clinical trials of long-acting ART in people with HIV who had previously achieved viral suppression on daily oral ART.
“Our patient population does not look like the patient population that got enrolled in the clinical trials to determine the approval criteria for long-acting ART,” Dr. Gandhi said in presenting the findings.
“If 10% of the population carries 90% of the HIV virus – which we see in modeling – then we need innovations for this population if we want to end the HIV epidemic,” she added.
“We tried long-acting ART in our diverse, urban, low-income population and we saw very high virologic suppression rates equal to those that were seen in the clinical trials,” Dr. Ghandi reported. “This shows that long-acting ART, used creatively and used boldly, could really make a dent in the [efforts] to end the HIV epidemic movement.”
Commenting on the study in a press statement, Nora Volkow, MD, director of the National Institute on Drug Abuse, said “Dr. Gandhi and her team have made state-of-the-art HIV treatment finally available to people with unique challenges, like those who use drugs, and have found success.”
“This is the sweet spot for addressing HIV – thinking outside the box to deliver care in a way that meets people’s needs, even when that means it happens outside the clinic walls, by phone, or on neighborhood streets,” she said. “This can be done, but it requires creativity and resolve.”
Twice-yearly dosing option?
Looking ahead, an even more intriguing scenario of a long-acting ART requiring injections only once every 6 months may be getting closer to fruition. Researchers at CROI 2023 reported early but promising safety and efficacy results of an innovative combination of the first-in-class HIV-1 capsid inhibitor lenacapavir with teropavimab and zinlirvimab, two broadly neutralizing antibodies (bNAbs).
To achieve the goal of the longer-acting therapy, Joseph J. Eron, MD, of the University of North Carolina at Chapel Hill, and colleagues modified both antibodies to extend their half-lives and allow less-frequent dosing.
For the phase 1b trial, 20 adult patients with virologically suppressed HIV for at least 18 months were randomly assigned to one of two doses of the ART, both groups receiving lenacapavir at 927 mg subcutaneous after oral loading, plus teropavimab (30 mg/kg IV) and zinlirvimab at either 10 mg/kg or 30 mg/kg.
Patients had to have a CD4 count greater than 500 and CD4 nadir greater than 350, and importantly, patients had to demonstrate sensitivity on DNA phenotyping to both bNAbs at baseline.
After 26 weeks, 18 of the 20 participants (90%) maintained a viral suppression of HIV-1 RNA less than 50 copies/mL.
Of the remaining two patients, one in the 10–mg/kg zinlirvimab group had a confirmed HIV RNA of 50 c/mL (155 copies/mL, confirmed 524 copies/mL) at week 16 and was able to be resuppressed with reinitiation of baseline ART, and one participant in the zinlirvimab 30 mg/kg group withdrew consent at week 12, with viral suppression, and chose to go back on oral therapy
The safety profile looked favorable, with no serious adverse events and two patients with grade 3 AEs, including one experiencing an injection site cellulitis and one with injection site erythema.
Dr. Eron noted that “bNAb sensitivity is an important issue and a limitation for broad use, [because] only about 50% of people with HIV in the U.S. would be sensitive to both antibodies.”
However, “we are doing a pilot of only 10 participants looking to see if it works with sensitivity to a single antibody, which would increase [applicability] to about 90% of people with HIV,” he said in an interview.
At a press conference, Dr. Eron commented on how far HIV treatment has come, from the early days of patients having to wake up every 4 hours to take their medication, then to having to take 15-20 pills a day, to the current option of long-acting ART every other month, and now the potential of just a twice-yearly treatment.
“This is a very preliminary proof-of-concept study and not a very large study, but I think it’s incredibly important,” he said.
The SOLAR study was funded by ViiV Healthcare. Dr. Ramgopal has received speaking and/or consulting fees from AbbVie, Gilead Sciences, Janssen, Merck, and ViiV Healthcare. Dr. Eron’s study was funded by Gilead Sciences.
A version of this article first appeared on Medscape.com.
as is typically required before initiation, results from two new studies suggest.
Meanwhile, a third study shows early promise of a long-acting ART regimen that could require injections only twice yearly.
“Instead of having the burden of taking a pill every day, patients with HIV can now have these choices of being able to forget about their treatment for up to 2 months at a time,” Moti N. Ramgopal, MD, first author of one of the three studies, said in a press conference at the Conference on Retroviruses and Opportunistic Infections. “My patients tell me that it’s game-changing for them.”
First head-to-head comparison
The injectable intramuscular combination of cabotegravir and rilpivirine, administered once every 1 or 2 months, is the first and only long-acting ART to be approved by the Food and Drug Administration for people with HIV. At the meeting, Dr. Ramgopal, from the Midway Immunology and Research Center in Fort Pierce, Fla., reported the results from the first head-to-head study comparing the regimen with the standard daily oral regimen of bictegravir/emtricitabine/tenofovir alafenamide (B/FTC/TAF).
For the phase 3b SOLAR trial, adults with HIV who were already virologically suppressed and treated with daily B/FTC/TAF were randomly assigned to remain on the oral regimen (n = 223) or switch to the long-acting injections every 2 months, either with an oral lead-in (n = 173) or without a lead-in (n = 274).
The results after 12 months showed noninferiority between the groups, with 90% of the long-acting ART group and 93% in the oral daily pill group maintaining viral suppression, defined as plasma HIV-1 RNA less than 50 copies/mL.
Two patients (0.4%) receiving the long-acting ART in a modified-intention to treat and 3 (0.6%) in the intention-to-treat populations had confirmed virologic failure, and rates of adverse events leading to withdrawal were 6% with the long-acting ART group versus 1% with the oral treatment group.
As many as 90% of subjects reported preferring the long-acting ART over their previous oral therapy at the end of the study, and those in the long-acting group also reported significantly greater improvements in quality of life on the HIV Treatment Satisfaction Questionnaire status version compared with the oral therapy group at the end of the study (P < .001).
Prior to the randomization, as many as 47% of patients on the oral regimen reported “always” or “often” having psychosocial challenges with the daily therapy, including worries of having their HIV status revealed and forgetting to take the medication.
“These data demonstrate that [the long-acting regimen] addresses important unmet needs for people with HIV who are virally suppressed on oral daily HIV therapy, while improving the quality of life,” said Dr. Ramgopal.
Suppression at onset not necessarily required
For all of its benefits, a key caveat of the cabotegravir and rilpivirine long-acting regimen is that it is approved only for patients who have already achieved viral suppression and are currently on oral ART, meaning some of the people most in need, including those with unstable housing, mental illness, or substance abuse disorders, may be excluded.
To evaluate the therapy’s efficacy among those patient types, Monica Gandhi, MD, MPH, professor of medicine and associate division chief at the University of California, San Francisco, enrolled 133 participants between June 2021 and November 2022 at the Ward 86 HIV Clinic, a safety-net clinic in San Francisco, to initiate long-acting ART. Participants included 57 patients (43%) with untreated or unsuppressed HIV, and 76 who were virally suppressed on oral ART.
Of the whole study group, 66% reported unstable housing, 8% reported experiencing homelessness, 38% reported having a mental illness, and 33% reported substance use.
Although all of the subjects (100%) who started with viral suppression remained suppressed over the study’s 26-week follow-up, the rate of viral suppression at the study’s end was nearly as high – 55 of 57 subjects (96.5%) – among those who started long-acting ART without having viral suppression.
Of note, the overall rate of study participants who did not achieve or maintain viral suppression (1.5%) was consistent with rates reported in clinical trials of long-acting ART in people with HIV who had previously achieved viral suppression on daily oral ART.
“Our patient population does not look like the patient population that got enrolled in the clinical trials to determine the approval criteria for long-acting ART,” Dr. Gandhi said in presenting the findings.
“If 10% of the population carries 90% of the HIV virus – which we see in modeling – then we need innovations for this population if we want to end the HIV epidemic,” she added.
“We tried long-acting ART in our diverse, urban, low-income population and we saw very high virologic suppression rates equal to those that were seen in the clinical trials,” Dr. Ghandi reported. “This shows that long-acting ART, used creatively and used boldly, could really make a dent in the [efforts] to end the HIV epidemic movement.”
Commenting on the study in a press statement, Nora Volkow, MD, director of the National Institute on Drug Abuse, said “Dr. Gandhi and her team have made state-of-the-art HIV treatment finally available to people with unique challenges, like those who use drugs, and have found success.”
“This is the sweet spot for addressing HIV – thinking outside the box to deliver care in a way that meets people’s needs, even when that means it happens outside the clinic walls, by phone, or on neighborhood streets,” she said. “This can be done, but it requires creativity and resolve.”
Twice-yearly dosing option?
Looking ahead, an even more intriguing scenario of a long-acting ART requiring injections only once every 6 months may be getting closer to fruition. Researchers at CROI 2023 reported early but promising safety and efficacy results of an innovative combination of the first-in-class HIV-1 capsid inhibitor lenacapavir with teropavimab and zinlirvimab, two broadly neutralizing antibodies (bNAbs).
To achieve the goal of the longer-acting therapy, Joseph J. Eron, MD, of the University of North Carolina at Chapel Hill, and colleagues modified both antibodies to extend their half-lives and allow less-frequent dosing.
For the phase 1b trial, 20 adult patients with virologically suppressed HIV for at least 18 months were randomly assigned to one of two doses of the ART, both groups receiving lenacapavir at 927 mg subcutaneous after oral loading, plus teropavimab (30 mg/kg IV) and zinlirvimab at either 10 mg/kg or 30 mg/kg.
Patients had to have a CD4 count greater than 500 and CD4 nadir greater than 350, and importantly, patients had to demonstrate sensitivity on DNA phenotyping to both bNAbs at baseline.
After 26 weeks, 18 of the 20 participants (90%) maintained a viral suppression of HIV-1 RNA less than 50 copies/mL.
Of the remaining two patients, one in the 10–mg/kg zinlirvimab group had a confirmed HIV RNA of 50 c/mL (155 copies/mL, confirmed 524 copies/mL) at week 16 and was able to be resuppressed with reinitiation of baseline ART, and one participant in the zinlirvimab 30 mg/kg group withdrew consent at week 12, with viral suppression, and chose to go back on oral therapy
The safety profile looked favorable, with no serious adverse events and two patients with grade 3 AEs, including one experiencing an injection site cellulitis and one with injection site erythema.
Dr. Eron noted that “bNAb sensitivity is an important issue and a limitation for broad use, [because] only about 50% of people with HIV in the U.S. would be sensitive to both antibodies.”
However, “we are doing a pilot of only 10 participants looking to see if it works with sensitivity to a single antibody, which would increase [applicability] to about 90% of people with HIV,” he said in an interview.
At a press conference, Dr. Eron commented on how far HIV treatment has come, from the early days of patients having to wake up every 4 hours to take their medication, then to having to take 15-20 pills a day, to the current option of long-acting ART every other month, and now the potential of just a twice-yearly treatment.
“This is a very preliminary proof-of-concept study and not a very large study, but I think it’s incredibly important,” he said.
The SOLAR study was funded by ViiV Healthcare. Dr. Ramgopal has received speaking and/or consulting fees from AbbVie, Gilead Sciences, Janssen, Merck, and ViiV Healthcare. Dr. Eron’s study was funded by Gilead Sciences.
A version of this article first appeared on Medscape.com.
as is typically required before initiation, results from two new studies suggest.
Meanwhile, a third study shows early promise of a long-acting ART regimen that could require injections only twice yearly.
“Instead of having the burden of taking a pill every day, patients with HIV can now have these choices of being able to forget about their treatment for up to 2 months at a time,” Moti N. Ramgopal, MD, first author of one of the three studies, said in a press conference at the Conference on Retroviruses and Opportunistic Infections. “My patients tell me that it’s game-changing for them.”
First head-to-head comparison
The injectable intramuscular combination of cabotegravir and rilpivirine, administered once every 1 or 2 months, is the first and only long-acting ART to be approved by the Food and Drug Administration for people with HIV. At the meeting, Dr. Ramgopal, from the Midway Immunology and Research Center in Fort Pierce, Fla., reported the results from the first head-to-head study comparing the regimen with the standard daily oral regimen of bictegravir/emtricitabine/tenofovir alafenamide (B/FTC/TAF).
For the phase 3b SOLAR trial, adults with HIV who were already virologically suppressed and treated with daily B/FTC/TAF were randomly assigned to remain on the oral regimen (n = 223) or switch to the long-acting injections every 2 months, either with an oral lead-in (n = 173) or without a lead-in (n = 274).
The results after 12 months showed noninferiority between the groups, with 90% of the long-acting ART group and 93% in the oral daily pill group maintaining viral suppression, defined as plasma HIV-1 RNA less than 50 copies/mL.
Two patients (0.4%) receiving the long-acting ART in a modified-intention to treat and 3 (0.6%) in the intention-to-treat populations had confirmed virologic failure, and rates of adverse events leading to withdrawal were 6% with the long-acting ART group versus 1% with the oral treatment group.
As many as 90% of subjects reported preferring the long-acting ART over their previous oral therapy at the end of the study, and those in the long-acting group also reported significantly greater improvements in quality of life on the HIV Treatment Satisfaction Questionnaire status version compared with the oral therapy group at the end of the study (P < .001).
Prior to the randomization, as many as 47% of patients on the oral regimen reported “always” or “often” having psychosocial challenges with the daily therapy, including worries of having their HIV status revealed and forgetting to take the medication.
“These data demonstrate that [the long-acting regimen] addresses important unmet needs for people with HIV who are virally suppressed on oral daily HIV therapy, while improving the quality of life,” said Dr. Ramgopal.
Suppression at onset not necessarily required
For all of its benefits, a key caveat of the cabotegravir and rilpivirine long-acting regimen is that it is approved only for patients who have already achieved viral suppression and are currently on oral ART, meaning some of the people most in need, including those with unstable housing, mental illness, or substance abuse disorders, may be excluded.
To evaluate the therapy’s efficacy among those patient types, Monica Gandhi, MD, MPH, professor of medicine and associate division chief at the University of California, San Francisco, enrolled 133 participants between June 2021 and November 2022 at the Ward 86 HIV Clinic, a safety-net clinic in San Francisco, to initiate long-acting ART. Participants included 57 patients (43%) with untreated or unsuppressed HIV, and 76 who were virally suppressed on oral ART.
Of the whole study group, 66% reported unstable housing, 8% reported experiencing homelessness, 38% reported having a mental illness, and 33% reported substance use.
Although all of the subjects (100%) who started with viral suppression remained suppressed over the study’s 26-week follow-up, the rate of viral suppression at the study’s end was nearly as high – 55 of 57 subjects (96.5%) – among those who started long-acting ART without having viral suppression.
Of note, the overall rate of study participants who did not achieve or maintain viral suppression (1.5%) was consistent with rates reported in clinical trials of long-acting ART in people with HIV who had previously achieved viral suppression on daily oral ART.
“Our patient population does not look like the patient population that got enrolled in the clinical trials to determine the approval criteria for long-acting ART,” Dr. Gandhi said in presenting the findings.
“If 10% of the population carries 90% of the HIV virus – which we see in modeling – then we need innovations for this population if we want to end the HIV epidemic,” she added.
“We tried long-acting ART in our diverse, urban, low-income population and we saw very high virologic suppression rates equal to those that were seen in the clinical trials,” Dr. Ghandi reported. “This shows that long-acting ART, used creatively and used boldly, could really make a dent in the [efforts] to end the HIV epidemic movement.”
Commenting on the study in a press statement, Nora Volkow, MD, director of the National Institute on Drug Abuse, said “Dr. Gandhi and her team have made state-of-the-art HIV treatment finally available to people with unique challenges, like those who use drugs, and have found success.”
“This is the sweet spot for addressing HIV – thinking outside the box to deliver care in a way that meets people’s needs, even when that means it happens outside the clinic walls, by phone, or on neighborhood streets,” she said. “This can be done, but it requires creativity and resolve.”
Twice-yearly dosing option?
Looking ahead, an even more intriguing scenario of a long-acting ART requiring injections only once every 6 months may be getting closer to fruition. Researchers at CROI 2023 reported early but promising safety and efficacy results of an innovative combination of the first-in-class HIV-1 capsid inhibitor lenacapavir with teropavimab and zinlirvimab, two broadly neutralizing antibodies (bNAbs).
To achieve the goal of the longer-acting therapy, Joseph J. Eron, MD, of the University of North Carolina at Chapel Hill, and colleagues modified both antibodies to extend their half-lives and allow less-frequent dosing.
For the phase 1b trial, 20 adult patients with virologically suppressed HIV for at least 18 months were randomly assigned to one of two doses of the ART, both groups receiving lenacapavir at 927 mg subcutaneous after oral loading, plus teropavimab (30 mg/kg IV) and zinlirvimab at either 10 mg/kg or 30 mg/kg.
Patients had to have a CD4 count greater than 500 and CD4 nadir greater than 350, and importantly, patients had to demonstrate sensitivity on DNA phenotyping to both bNAbs at baseline.
After 26 weeks, 18 of the 20 participants (90%) maintained a viral suppression of HIV-1 RNA less than 50 copies/mL.
Of the remaining two patients, one in the 10–mg/kg zinlirvimab group had a confirmed HIV RNA of 50 c/mL (155 copies/mL, confirmed 524 copies/mL) at week 16 and was able to be resuppressed with reinitiation of baseline ART, and one participant in the zinlirvimab 30 mg/kg group withdrew consent at week 12, with viral suppression, and chose to go back on oral therapy
The safety profile looked favorable, with no serious adverse events and two patients with grade 3 AEs, including one experiencing an injection site cellulitis and one with injection site erythema.
Dr. Eron noted that “bNAb sensitivity is an important issue and a limitation for broad use, [because] only about 50% of people with HIV in the U.S. would be sensitive to both antibodies.”
However, “we are doing a pilot of only 10 participants looking to see if it works with sensitivity to a single antibody, which would increase [applicability] to about 90% of people with HIV,” he said in an interview.
At a press conference, Dr. Eron commented on how far HIV treatment has come, from the early days of patients having to wake up every 4 hours to take their medication, then to having to take 15-20 pills a day, to the current option of long-acting ART every other month, and now the potential of just a twice-yearly treatment.
“This is a very preliminary proof-of-concept study and not a very large study, but I think it’s incredibly important,” he said.
The SOLAR study was funded by ViiV Healthcare. Dr. Ramgopal has received speaking and/or consulting fees from AbbVie, Gilead Sciences, Janssen, Merck, and ViiV Healthcare. Dr. Eron’s study was funded by Gilead Sciences.
A version of this article first appeared on Medscape.com.
FROM CROI 2023
Doxy PEP does not lower risk of STIs in cisgender women
The benefits of doxycycline postexposure prophylaxis (Doxy PEP) in preventing the transmission of sexually transmitted infections (STIs) in men and transgender women do not appear to extend to cisgender women, who have disproportionately high rates of infection in many regions.
“This was the first trial to evaluate doxycycline PEP for cisgender women,” said first author Jenell Stewart, DO, of the University of Minnesota, Minneapolis, in discussing the findings at a press conference at the Conference on Retroviruses & Opportunistic Infections.
“Unfortunately, our primary outcome was not statistically significant – we did not see a reduction in STIs among cisgender women, which is in stark contrast to [reported effects] among cisgender men and transgender women,” she said.
The findings are from a study of 449 nonpregnant cisgender women (mean age, 24 years) in Kenya who had been taking daily oral HIV preexposure prophylaxis (PrEP) for a median of about 7 months.
The women were randomly assigned to receive either Doxy PEP 200 mg, to be taken within 72 hours of sex (n = 224), or standard care, which included quarterly screening and treatment of STIs (n = 225).
Of the women, 36.7% reported transactional sex at enrollment; their baseline prevalence of STIs was 17.9%, including 14.1% with chlamydia, 3.8% gonorrhea, and 0.4% syphilis. There were no differences between the study groups.
In surveys, 78% of the women reported adherence to the use of Doxy PEP; they took the prophylaxis at least as many days as they had sex.
Nevertheless, there was no significant difference in the incidence of STIs, reported over 1 year, at quarterly visits that included genital STI testing, between groups, with 50 patients in the Doxy PEP group and 59 in the standard screening group developing STIs (relative risk, 0.88; P = .51).
Of the infections, 85 were chlamydia, including 35 in the Doxy PEP group and 50 with standard of care, while 31 were gonorrhea, including 19 in the Doxy PEP group and 12 with standard of care; 8 had both infections, and there was 1 syphilis infection.
The results were consistent across subanalyses of patients grouped according to STI, who became pregnant (n = 80), or sorted by other factors including age, contraceptive use, transactional sex, and STI at baseline.
None of the women developed HIV, and there were no serious events associated with the Doxy PEP treatment.
Cisgender women bear ‘highest burden’ of STIs
The findings are disappointing in light of the higher rates of STIs among cisgender women, with the Centers for Disease Control and Prevention reporting that women also disproportionately bear the long-term consequences of STIs.
“For example, each year, untreated sexually transmitted diseases cause infertility in at least 20,000 women in the United States, and a pregnant woman is highly likely to pass syphilis unto her unborn baby if left untested or untreated,” the CDC reports.
The STI rates are particularly high for women taking HIV PrEP in regions like East Africa, where rates of STIs among cisgender women in many cases are higher than rates for men taking PrEP in high income countries, Dr. Stewart said.
Previous studies of Doxy PEP in men and transgender women taking HIV PrEP, including new research presented at CROI, have shown highly encouraging reductions in STIs, at rates of up to approximately 80% for chlamydia and syphilis.
Adherence, anatomy, resistance
The key theories for the lack of a prevention of infections in cisgender women surround the issues of resistances, as well as anatomy and adherence, said Dr. Stewart.
In terms of bacterial resistances, while initial testing in a limited number of samples the study found no evidence of markers of resistance for chlamydia, all of the gonorrhea samples did show tetracycline-resistant N gonorrhea at baseline and follow-up in both groups.
Regarding anatomic differences, doxycycline may not prevent STIs in endocervical tissue among cisgender women, Dr. Stewart noted. Women are known to be at higher risk of infection because the lining of the vagina is thinner than the skin of the penis, allowing for easier penetration of bacteria and viruses.
The study was designed to optimize adherence to Doxy PEP. Measures included monitoring with weekly text message surveys, in which the women reported a high rate of adherence.
The overall retention rate in the study was high; as many as 97% of the quarterly follow-up visits were completed, including 95% in the Doxy PEP group and 98% of the standard care group. The response rate for the weekly surveys was 81%.
Of note, women reported the use of the treatment to be “imperfect,” suggesting social problems, such as biases toward the use of the prophylaxis.
The results underscore the need for ongoing efforts to make sure no groups of patients are left behind as interventions advance, Dr. Stewart said.
“The burden of STIs on cisgender women is large and growing,” she concluded. “STI prevention interventions are needed.”
Commenting on the study, Renee A. Heffron, PhD, MPH, said the findings “are somewhat surprising because results from trials in other populations have been positive.
“But cisgender women are exposed through the cervix, and this tissue is different from rectal or urethral tissue,” Dr. Heffron, a professor at the department of medicine and director of the Center for AIDS Research at the University of Alabama, Birmingham, told this news organization.
Further findings from the research should help shed light on key issues of adherence and drug concentration levels in cervical tissue, she added.
“For cisgender women, these data are the first and the beginning of understanding whether this is a viable strategy,” Dr. Heffron said.
“We have more to learn to better understand the results from the trial main outcomes, and if there are tweaks to this strategy that would improve efficacy.”
The authors and Dr. Heffron have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The benefits of doxycycline postexposure prophylaxis (Doxy PEP) in preventing the transmission of sexually transmitted infections (STIs) in men and transgender women do not appear to extend to cisgender women, who have disproportionately high rates of infection in many regions.
“This was the first trial to evaluate doxycycline PEP for cisgender women,” said first author Jenell Stewart, DO, of the University of Minnesota, Minneapolis, in discussing the findings at a press conference at the Conference on Retroviruses & Opportunistic Infections.
“Unfortunately, our primary outcome was not statistically significant – we did not see a reduction in STIs among cisgender women, which is in stark contrast to [reported effects] among cisgender men and transgender women,” she said.
The findings are from a study of 449 nonpregnant cisgender women (mean age, 24 years) in Kenya who had been taking daily oral HIV preexposure prophylaxis (PrEP) for a median of about 7 months.
The women were randomly assigned to receive either Doxy PEP 200 mg, to be taken within 72 hours of sex (n = 224), or standard care, which included quarterly screening and treatment of STIs (n = 225).
Of the women, 36.7% reported transactional sex at enrollment; their baseline prevalence of STIs was 17.9%, including 14.1% with chlamydia, 3.8% gonorrhea, and 0.4% syphilis. There were no differences between the study groups.
In surveys, 78% of the women reported adherence to the use of Doxy PEP; they took the prophylaxis at least as many days as they had sex.
Nevertheless, there was no significant difference in the incidence of STIs, reported over 1 year, at quarterly visits that included genital STI testing, between groups, with 50 patients in the Doxy PEP group and 59 in the standard screening group developing STIs (relative risk, 0.88; P = .51).
Of the infections, 85 were chlamydia, including 35 in the Doxy PEP group and 50 with standard of care, while 31 were gonorrhea, including 19 in the Doxy PEP group and 12 with standard of care; 8 had both infections, and there was 1 syphilis infection.
The results were consistent across subanalyses of patients grouped according to STI, who became pregnant (n = 80), or sorted by other factors including age, contraceptive use, transactional sex, and STI at baseline.
None of the women developed HIV, and there were no serious events associated with the Doxy PEP treatment.
Cisgender women bear ‘highest burden’ of STIs
The findings are disappointing in light of the higher rates of STIs among cisgender women, with the Centers for Disease Control and Prevention reporting that women also disproportionately bear the long-term consequences of STIs.
“For example, each year, untreated sexually transmitted diseases cause infertility in at least 20,000 women in the United States, and a pregnant woman is highly likely to pass syphilis unto her unborn baby if left untested or untreated,” the CDC reports.
The STI rates are particularly high for women taking HIV PrEP in regions like East Africa, where rates of STIs among cisgender women in many cases are higher than rates for men taking PrEP in high income countries, Dr. Stewart said.
Previous studies of Doxy PEP in men and transgender women taking HIV PrEP, including new research presented at CROI, have shown highly encouraging reductions in STIs, at rates of up to approximately 80% for chlamydia and syphilis.
Adherence, anatomy, resistance
The key theories for the lack of a prevention of infections in cisgender women surround the issues of resistances, as well as anatomy and adherence, said Dr. Stewart.
In terms of bacterial resistances, while initial testing in a limited number of samples the study found no evidence of markers of resistance for chlamydia, all of the gonorrhea samples did show tetracycline-resistant N gonorrhea at baseline and follow-up in both groups.
Regarding anatomic differences, doxycycline may not prevent STIs in endocervical tissue among cisgender women, Dr. Stewart noted. Women are known to be at higher risk of infection because the lining of the vagina is thinner than the skin of the penis, allowing for easier penetration of bacteria and viruses.
The study was designed to optimize adherence to Doxy PEP. Measures included monitoring with weekly text message surveys, in which the women reported a high rate of adherence.
The overall retention rate in the study was high; as many as 97% of the quarterly follow-up visits were completed, including 95% in the Doxy PEP group and 98% of the standard care group. The response rate for the weekly surveys was 81%.
Of note, women reported the use of the treatment to be “imperfect,” suggesting social problems, such as biases toward the use of the prophylaxis.
The results underscore the need for ongoing efforts to make sure no groups of patients are left behind as interventions advance, Dr. Stewart said.
“The burden of STIs on cisgender women is large and growing,” she concluded. “STI prevention interventions are needed.”
Commenting on the study, Renee A. Heffron, PhD, MPH, said the findings “are somewhat surprising because results from trials in other populations have been positive.
“But cisgender women are exposed through the cervix, and this tissue is different from rectal or urethral tissue,” Dr. Heffron, a professor at the department of medicine and director of the Center for AIDS Research at the University of Alabama, Birmingham, told this news organization.
Further findings from the research should help shed light on key issues of adherence and drug concentration levels in cervical tissue, she added.
“For cisgender women, these data are the first and the beginning of understanding whether this is a viable strategy,” Dr. Heffron said.
“We have more to learn to better understand the results from the trial main outcomes, and if there are tweaks to this strategy that would improve efficacy.”
The authors and Dr. Heffron have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The benefits of doxycycline postexposure prophylaxis (Doxy PEP) in preventing the transmission of sexually transmitted infections (STIs) in men and transgender women do not appear to extend to cisgender women, who have disproportionately high rates of infection in many regions.
“This was the first trial to evaluate doxycycline PEP for cisgender women,” said first author Jenell Stewart, DO, of the University of Minnesota, Minneapolis, in discussing the findings at a press conference at the Conference on Retroviruses & Opportunistic Infections.
“Unfortunately, our primary outcome was not statistically significant – we did not see a reduction in STIs among cisgender women, which is in stark contrast to [reported effects] among cisgender men and transgender women,” she said.
The findings are from a study of 449 nonpregnant cisgender women (mean age, 24 years) in Kenya who had been taking daily oral HIV preexposure prophylaxis (PrEP) for a median of about 7 months.
The women were randomly assigned to receive either Doxy PEP 200 mg, to be taken within 72 hours of sex (n = 224), or standard care, which included quarterly screening and treatment of STIs (n = 225).
Of the women, 36.7% reported transactional sex at enrollment; their baseline prevalence of STIs was 17.9%, including 14.1% with chlamydia, 3.8% gonorrhea, and 0.4% syphilis. There were no differences between the study groups.
In surveys, 78% of the women reported adherence to the use of Doxy PEP; they took the prophylaxis at least as many days as they had sex.
Nevertheless, there was no significant difference in the incidence of STIs, reported over 1 year, at quarterly visits that included genital STI testing, between groups, with 50 patients in the Doxy PEP group and 59 in the standard screening group developing STIs (relative risk, 0.88; P = .51).
Of the infections, 85 were chlamydia, including 35 in the Doxy PEP group and 50 with standard of care, while 31 were gonorrhea, including 19 in the Doxy PEP group and 12 with standard of care; 8 had both infections, and there was 1 syphilis infection.
The results were consistent across subanalyses of patients grouped according to STI, who became pregnant (n = 80), or sorted by other factors including age, contraceptive use, transactional sex, and STI at baseline.
None of the women developed HIV, and there were no serious events associated with the Doxy PEP treatment.
Cisgender women bear ‘highest burden’ of STIs
The findings are disappointing in light of the higher rates of STIs among cisgender women, with the Centers for Disease Control and Prevention reporting that women also disproportionately bear the long-term consequences of STIs.
“For example, each year, untreated sexually transmitted diseases cause infertility in at least 20,000 women in the United States, and a pregnant woman is highly likely to pass syphilis unto her unborn baby if left untested or untreated,” the CDC reports.
The STI rates are particularly high for women taking HIV PrEP in regions like East Africa, where rates of STIs among cisgender women in many cases are higher than rates for men taking PrEP in high income countries, Dr. Stewart said.
Previous studies of Doxy PEP in men and transgender women taking HIV PrEP, including new research presented at CROI, have shown highly encouraging reductions in STIs, at rates of up to approximately 80% for chlamydia and syphilis.
Adherence, anatomy, resistance
The key theories for the lack of a prevention of infections in cisgender women surround the issues of resistances, as well as anatomy and adherence, said Dr. Stewart.
In terms of bacterial resistances, while initial testing in a limited number of samples the study found no evidence of markers of resistance for chlamydia, all of the gonorrhea samples did show tetracycline-resistant N gonorrhea at baseline and follow-up in both groups.
Regarding anatomic differences, doxycycline may not prevent STIs in endocervical tissue among cisgender women, Dr. Stewart noted. Women are known to be at higher risk of infection because the lining of the vagina is thinner than the skin of the penis, allowing for easier penetration of bacteria and viruses.
The study was designed to optimize adherence to Doxy PEP. Measures included monitoring with weekly text message surveys, in which the women reported a high rate of adherence.
The overall retention rate in the study was high; as many as 97% of the quarterly follow-up visits were completed, including 95% in the Doxy PEP group and 98% of the standard care group. The response rate for the weekly surveys was 81%.
Of note, women reported the use of the treatment to be “imperfect,” suggesting social problems, such as biases toward the use of the prophylaxis.
The results underscore the need for ongoing efforts to make sure no groups of patients are left behind as interventions advance, Dr. Stewart said.
“The burden of STIs on cisgender women is large and growing,” she concluded. “STI prevention interventions are needed.”
Commenting on the study, Renee A. Heffron, PhD, MPH, said the findings “are somewhat surprising because results from trials in other populations have been positive.
“But cisgender women are exposed through the cervix, and this tissue is different from rectal or urethral tissue,” Dr. Heffron, a professor at the department of medicine and director of the Center for AIDS Research at the University of Alabama, Birmingham, told this news organization.
Further findings from the research should help shed light on key issues of adherence and drug concentration levels in cervical tissue, she added.
“For cisgender women, these data are the first and the beginning of understanding whether this is a viable strategy,” Dr. Heffron said.
“We have more to learn to better understand the results from the trial main outcomes, and if there are tweaks to this strategy that would improve efficacy.”
The authors and Dr. Heffron have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CROI 2023
Meningococcal vaccine shows benefit in STI prevention
The latest study to show high efficacy of doxycycline post-exposure prophylaxis (Doxy PEP) in preventing sexually transmitted infections among men who have sex with men (MSM) adds a new twist, showing – for the first time – reductions in gonorrhea among those receiving the meningococcal B vaccine.
said first author Jean-Michel Molina, MD, PhD, in presenting the findings at the Conference on Retroviruses and Opportunistic Infections.
In addition, “two doses of the meningococcal B vaccine reduced the incidence of a first episode of gonorrhea by roughly 50% among men who have sex with men,” said Dr. Molina, a professor of infectious diseases at the University of Paris, and head of the Infectious Diseases Department at the Saint-Louis and Lariboisière Hospitals, Paris.
Whereas the advent of PrEP has been associated with significant reductions in HIV transmission, rates of STIs have conversely been on the rise among MSM, specifically among those receiving PrEP.
Post-exposure prophylaxis with Doxy PEP has been shown to reduce the incidence of chlamydia and syphilis by approximately 70%; however, effects on prevention of gonorrhea have been less clear.
Meningococcal B vaccination has, meanwhile, shown intriguing reductions of gonorrhea incidence of as much as 26%-46% in some observational studies.
Therefore, Dr. Molina and colleagues decided to further investigate Doxy PEP as well as the meningococcal B vaccine in prevention of STIs.
For the ANRS 174 DOXYVAC trial, they enrolled 546 MSM in the open-label, multicenter study between January 2021 and July 2022.
The men were randomly assigned to one of 4 groups: doxycycline postexposure prophylaxis (Doxy PEP: 200 mg; n = 332), no Doxy PEP (n = 170), two shots of meningococcal B vaccine (4CMenB vaccine; n = 257), or no 4CMenB vaccine (n = 245).
All participants were assigned to their groups within 72 hours of condomless sex.
The men, who had a median age of 39, had a median time of PrEP use of 42 months, a history of an STI in the past year, and their median number of sexual partners in the past 3 months was 10.
Their characteristics were well-balanced across the treatment groups. After discontinuations of 54 patients across the groups, the final analysis included 502 participants.
With a median follow-up of 9 months, the intent-to-treat analysis showed 13 subjects had a first episode of chlamydia or syphilis in the Doxy PEP group, versus 49 subjects infected in the no Doxy PEP arm, for an incidence of 5.6 versus 35.4 per 100 person-years, respectively (adjusted hazard ratio, 0.16; P < .0001).
Infection specifically with chlamydia occurred among 21 men with no Doxy PEP versus 5 receiving Dox PEP (19.3 vs. 2.1 per 100 person-years, respectively; HR, 0.11; P < .0001).
And infection with syphilis occurred in 18 men receiving no Doxy PEP versus 8 receiving the treatment (16.3 vs. 3.4 per 100 person-years, respectively; HR, 0.21; P < .001).
The corresponding rates for gonorrhea infection were an incidence 41.3 versus 20.5 per 100 person-years, in the no Doxy PEP versus Doxy PEP arms, respectively (adjusted HR, 0.49; P = .001), and 29.4 versus 16.8 per 100 person-years for Mycoplasma genitalium infection (aHR, 0.55; P = .015).
Throughout the study, about 80% of patients in the Doxy PEP group reported using the prophylaxis treatment after their most recent sexual intercourse, with subjects reporting taking a median of seven pills per month.
In the vaccine/no vaccine comparisons, 32 subjects in the no meningococcal vaccine group were infected with a first gonorrhea infection, compared with 17 in the vaccine group, representing an incidence of 19.7 versus 9.8 per 100 person-years, respectively (adjusted HR, 0.49; P = .016), which Dr. Molina called “highly significant.”
An analysis of the cumulative incidence of gonorrhea infection with the meningococcal vaccine showed rates in the no vaccine versus vaccine groups of 30.4 versus 20.1 per 100 person-years, respectively; however, statistical significance was not reached (aHR, 0.66; P = .052).
Importantly, there were no significant interactions in the results between those receiving Doxy PEP or the 4CMenB vaccine group, and there were no significant differences in drug-related serious adverse events between the groups.
Dr. Molina noted that the meningococcal B vaccine is known to contain key antigens that are shared between meningitis and gonorrhea, which could explain the benefits.
Although chlamydia and syphilis thus far appear to remain susceptible to Doxy PEP, resistances with gonorrhea remain a concern, hence the ability of the vaccine to provide some protection could be an added bonus.
“We know that [gonorrhea] is able to very quickly develop resistances to any antibiotics, so that was why we wanted to look beyond the antibiotic prophylaxis,” said Dr. Molina.
Among questions to explore looking ahead is the potential longevity of protection with the vaccine.
“We don’t know at this point how long the protection with the vaccine could last, or if [people] may need booster injections, for instance, but the literature suggests benefits for at least a year,” Dr. Molina said. “We are still monitoring the patients in the study to see what happens.”
He added that combination of the interventions may be of benefit.
“In the future, we think we may need to combine these approaches if we want to meet the WHO/UNAIDS targets to reduce the incidence of HIV and STIs by 90% by 2030.”
Commenting on the study, CROI vice-chair Landon Myer, MD, PhD, noted that “gonorrhea develops resistance quickly and can be hard to treat or prophylaxis, so the vaccine finding, which was hinted at by previous observational data, is really important.”
He agrees that “the duration of protective efficacy – a big thing in vaccines – is unknown.”
“Still, this is really significant,” Dr. Myer stressed. “An efficacious vaccine against a stubborn sexually transmitted infection.”
A version of this article first appeared on Medscape.com.
The latest study to show high efficacy of doxycycline post-exposure prophylaxis (Doxy PEP) in preventing sexually transmitted infections among men who have sex with men (MSM) adds a new twist, showing – for the first time – reductions in gonorrhea among those receiving the meningococcal B vaccine.
said first author Jean-Michel Molina, MD, PhD, in presenting the findings at the Conference on Retroviruses and Opportunistic Infections.
In addition, “two doses of the meningococcal B vaccine reduced the incidence of a first episode of gonorrhea by roughly 50% among men who have sex with men,” said Dr. Molina, a professor of infectious diseases at the University of Paris, and head of the Infectious Diseases Department at the Saint-Louis and Lariboisière Hospitals, Paris.
Whereas the advent of PrEP has been associated with significant reductions in HIV transmission, rates of STIs have conversely been on the rise among MSM, specifically among those receiving PrEP.
Post-exposure prophylaxis with Doxy PEP has been shown to reduce the incidence of chlamydia and syphilis by approximately 70%; however, effects on prevention of gonorrhea have been less clear.
Meningococcal B vaccination has, meanwhile, shown intriguing reductions of gonorrhea incidence of as much as 26%-46% in some observational studies.
Therefore, Dr. Molina and colleagues decided to further investigate Doxy PEP as well as the meningococcal B vaccine in prevention of STIs.
For the ANRS 174 DOXYVAC trial, they enrolled 546 MSM in the open-label, multicenter study between January 2021 and July 2022.
The men were randomly assigned to one of 4 groups: doxycycline postexposure prophylaxis (Doxy PEP: 200 mg; n = 332), no Doxy PEP (n = 170), two shots of meningococcal B vaccine (4CMenB vaccine; n = 257), or no 4CMenB vaccine (n = 245).
All participants were assigned to their groups within 72 hours of condomless sex.
The men, who had a median age of 39, had a median time of PrEP use of 42 months, a history of an STI in the past year, and their median number of sexual partners in the past 3 months was 10.
Their characteristics were well-balanced across the treatment groups. After discontinuations of 54 patients across the groups, the final analysis included 502 participants.
With a median follow-up of 9 months, the intent-to-treat analysis showed 13 subjects had a first episode of chlamydia or syphilis in the Doxy PEP group, versus 49 subjects infected in the no Doxy PEP arm, for an incidence of 5.6 versus 35.4 per 100 person-years, respectively (adjusted hazard ratio, 0.16; P < .0001).
Infection specifically with chlamydia occurred among 21 men with no Doxy PEP versus 5 receiving Dox PEP (19.3 vs. 2.1 per 100 person-years, respectively; HR, 0.11; P < .0001).
And infection with syphilis occurred in 18 men receiving no Doxy PEP versus 8 receiving the treatment (16.3 vs. 3.4 per 100 person-years, respectively; HR, 0.21; P < .001).
The corresponding rates for gonorrhea infection were an incidence 41.3 versus 20.5 per 100 person-years, in the no Doxy PEP versus Doxy PEP arms, respectively (adjusted HR, 0.49; P = .001), and 29.4 versus 16.8 per 100 person-years for Mycoplasma genitalium infection (aHR, 0.55; P = .015).
Throughout the study, about 80% of patients in the Doxy PEP group reported using the prophylaxis treatment after their most recent sexual intercourse, with subjects reporting taking a median of seven pills per month.
In the vaccine/no vaccine comparisons, 32 subjects in the no meningococcal vaccine group were infected with a first gonorrhea infection, compared with 17 in the vaccine group, representing an incidence of 19.7 versus 9.8 per 100 person-years, respectively (adjusted HR, 0.49; P = .016), which Dr. Molina called “highly significant.”
An analysis of the cumulative incidence of gonorrhea infection with the meningococcal vaccine showed rates in the no vaccine versus vaccine groups of 30.4 versus 20.1 per 100 person-years, respectively; however, statistical significance was not reached (aHR, 0.66; P = .052).
Importantly, there were no significant interactions in the results between those receiving Doxy PEP or the 4CMenB vaccine group, and there were no significant differences in drug-related serious adverse events between the groups.
Dr. Molina noted that the meningococcal B vaccine is known to contain key antigens that are shared between meningitis and gonorrhea, which could explain the benefits.
Although chlamydia and syphilis thus far appear to remain susceptible to Doxy PEP, resistances with gonorrhea remain a concern, hence the ability of the vaccine to provide some protection could be an added bonus.
“We know that [gonorrhea] is able to very quickly develop resistances to any antibiotics, so that was why we wanted to look beyond the antibiotic prophylaxis,” said Dr. Molina.
Among questions to explore looking ahead is the potential longevity of protection with the vaccine.
“We don’t know at this point how long the protection with the vaccine could last, or if [people] may need booster injections, for instance, but the literature suggests benefits for at least a year,” Dr. Molina said. “We are still monitoring the patients in the study to see what happens.”
He added that combination of the interventions may be of benefit.
“In the future, we think we may need to combine these approaches if we want to meet the WHO/UNAIDS targets to reduce the incidence of HIV and STIs by 90% by 2030.”
Commenting on the study, CROI vice-chair Landon Myer, MD, PhD, noted that “gonorrhea develops resistance quickly and can be hard to treat or prophylaxis, so the vaccine finding, which was hinted at by previous observational data, is really important.”
He agrees that “the duration of protective efficacy – a big thing in vaccines – is unknown.”
“Still, this is really significant,” Dr. Myer stressed. “An efficacious vaccine against a stubborn sexually transmitted infection.”
A version of this article first appeared on Medscape.com.
The latest study to show high efficacy of doxycycline post-exposure prophylaxis (Doxy PEP) in preventing sexually transmitted infections among men who have sex with men (MSM) adds a new twist, showing – for the first time – reductions in gonorrhea among those receiving the meningococcal B vaccine.
said first author Jean-Michel Molina, MD, PhD, in presenting the findings at the Conference on Retroviruses and Opportunistic Infections.
In addition, “two doses of the meningococcal B vaccine reduced the incidence of a first episode of gonorrhea by roughly 50% among men who have sex with men,” said Dr. Molina, a professor of infectious diseases at the University of Paris, and head of the Infectious Diseases Department at the Saint-Louis and Lariboisière Hospitals, Paris.
Whereas the advent of PrEP has been associated with significant reductions in HIV transmission, rates of STIs have conversely been on the rise among MSM, specifically among those receiving PrEP.
Post-exposure prophylaxis with Doxy PEP has been shown to reduce the incidence of chlamydia and syphilis by approximately 70%; however, effects on prevention of gonorrhea have been less clear.
Meningococcal B vaccination has, meanwhile, shown intriguing reductions of gonorrhea incidence of as much as 26%-46% in some observational studies.
Therefore, Dr. Molina and colleagues decided to further investigate Doxy PEP as well as the meningococcal B vaccine in prevention of STIs.
For the ANRS 174 DOXYVAC trial, they enrolled 546 MSM in the open-label, multicenter study between January 2021 and July 2022.
The men were randomly assigned to one of 4 groups: doxycycline postexposure prophylaxis (Doxy PEP: 200 mg; n = 332), no Doxy PEP (n = 170), two shots of meningococcal B vaccine (4CMenB vaccine; n = 257), or no 4CMenB vaccine (n = 245).
All participants were assigned to their groups within 72 hours of condomless sex.
The men, who had a median age of 39, had a median time of PrEP use of 42 months, a history of an STI in the past year, and their median number of sexual partners in the past 3 months was 10.
Their characteristics were well-balanced across the treatment groups. After discontinuations of 54 patients across the groups, the final analysis included 502 participants.
With a median follow-up of 9 months, the intent-to-treat analysis showed 13 subjects had a first episode of chlamydia or syphilis in the Doxy PEP group, versus 49 subjects infected in the no Doxy PEP arm, for an incidence of 5.6 versus 35.4 per 100 person-years, respectively (adjusted hazard ratio, 0.16; P < .0001).
Infection specifically with chlamydia occurred among 21 men with no Doxy PEP versus 5 receiving Dox PEP (19.3 vs. 2.1 per 100 person-years, respectively; HR, 0.11; P < .0001).
And infection with syphilis occurred in 18 men receiving no Doxy PEP versus 8 receiving the treatment (16.3 vs. 3.4 per 100 person-years, respectively; HR, 0.21; P < .001).
The corresponding rates for gonorrhea infection were an incidence 41.3 versus 20.5 per 100 person-years, in the no Doxy PEP versus Doxy PEP arms, respectively (adjusted HR, 0.49; P = .001), and 29.4 versus 16.8 per 100 person-years for Mycoplasma genitalium infection (aHR, 0.55; P = .015).
Throughout the study, about 80% of patients in the Doxy PEP group reported using the prophylaxis treatment after their most recent sexual intercourse, with subjects reporting taking a median of seven pills per month.
In the vaccine/no vaccine comparisons, 32 subjects in the no meningococcal vaccine group were infected with a first gonorrhea infection, compared with 17 in the vaccine group, representing an incidence of 19.7 versus 9.8 per 100 person-years, respectively (adjusted HR, 0.49; P = .016), which Dr. Molina called “highly significant.”
An analysis of the cumulative incidence of gonorrhea infection with the meningococcal vaccine showed rates in the no vaccine versus vaccine groups of 30.4 versus 20.1 per 100 person-years, respectively; however, statistical significance was not reached (aHR, 0.66; P = .052).
Importantly, there were no significant interactions in the results between those receiving Doxy PEP or the 4CMenB vaccine group, and there were no significant differences in drug-related serious adverse events between the groups.
Dr. Molina noted that the meningococcal B vaccine is known to contain key antigens that are shared between meningitis and gonorrhea, which could explain the benefits.
Although chlamydia and syphilis thus far appear to remain susceptible to Doxy PEP, resistances with gonorrhea remain a concern, hence the ability of the vaccine to provide some protection could be an added bonus.
“We know that [gonorrhea] is able to very quickly develop resistances to any antibiotics, so that was why we wanted to look beyond the antibiotic prophylaxis,” said Dr. Molina.
Among questions to explore looking ahead is the potential longevity of protection with the vaccine.
“We don’t know at this point how long the protection with the vaccine could last, or if [people] may need booster injections, for instance, but the literature suggests benefits for at least a year,” Dr. Molina said. “We are still monitoring the patients in the study to see what happens.”
He added that combination of the interventions may be of benefit.
“In the future, we think we may need to combine these approaches if we want to meet the WHO/UNAIDS targets to reduce the incidence of HIV and STIs by 90% by 2030.”
Commenting on the study, CROI vice-chair Landon Myer, MD, PhD, noted that “gonorrhea develops resistance quickly and can be hard to treat or prophylaxis, so the vaccine finding, which was hinted at by previous observational data, is really important.”
He agrees that “the duration of protective efficacy – a big thing in vaccines – is unknown.”
“Still, this is really significant,” Dr. Myer stressed. “An efficacious vaccine against a stubborn sexually transmitted infection.”
A version of this article first appeared on Medscape.com.
FROM CROI 2023