User login
Vitamin D fails to stave off statin-related muscle symptoms
Vitamin D supplements do not prevent muscle symptoms in new statin users or affect the likelihood of discontinuing a statin due to muscle pain and discomfort, a substudy of the VITAL trial indicates.
Among more than 2,000 randomized participants, statin-associated muscle symptoms (SAMS) were reported by 31% assigned to vitamin D and 31% assigned to placebo.
The two groups were equally likely to stop taking a statin due to muscle symptoms, at 13%.
No significant difference was observed in SAMS (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.18) or statin discontinuations (OR, 1.04; 95% CI, 0.80-1.35) after adjustment for baseline variables and other characteristics, namely age, sex, and African-American race, previously found to be associated with SAMS in VITAL.
“We actually thought when we started out that maybe we were going to show something, that maybe it was going to be that the people who got the vitamin D were least likely to have a problem with a statin than all those who didn’t get vitamin D, but that is not what we showed,” senior author Neil J. Stone, MD, Northwestern University, Chicago, told this news organization.
He noted that patients in the clinic with low levels of vitamin D often have muscle pain and discomfort and that previous unblinded studies suggested vitamin D might benefit patients with SAMS and reduce statin intolerance.
As previously reported, the double-blind VITAL trial showed no difference in the primary prevention of cardiovascular disease or cancer at 5 years among 25,871 middle-aged adults randomized to vitamin D3 at 2000 IU/d or placebo, regardless of their baseline vitamin D level.
Unlike previous studies showing a benefit with vitamin D on SAMS, importantly, VITAL participants were unaware of whether they were taking vitamin D or placebo and were not expecting any help with their muscle symptoms, first author Mark A. Hlatky, MD, Stanford (Calif.) University, pointed out in an interview.
As to how many statin users turn to the popular supplement for SAMS, he said that number couldn’t be pinned down, despite a lengthy search. “But I think it’s very common, because up to half of people stop taking their statins within a year and many of these do so because of statin-associated muscle symptoms, and we found it in about 30% of people who have them. I have them myself and was motivated to study it because I thought this was an interesting question.”
The results were published online in JAMA Cardiology.
SAMS by baseline 25-OHD
The substudy included 2,083 patients who initiated statin therapy after randomization and were surveyed in early 2016 about their statin use and muscle symptoms.
Two-thirds, or 1,397 patients, had 25-hydroxy vitamin D (25-OHD) measured at baseline, with 47% having levels < 30 ng/mL and 13% levels < 20 ng/mL.
Serum 25-OHD levels were virtually identical in the two treatment groups (mean, 30.4 ng/mL; median, 30.0 ng/mL). The frequency of SAMS did not differ between those assigned to vitamin D or placebo (28% vs. 31%).
The odds ratios for the association with vitamin D on SAMS were:
- 0.86 in all respondents with 25-OHD measured (95% CI, 0.69-1.09).
- 0.87 in those with levels ≥ 30 ng/mL (95% CI, 0.64-1.19).
- 0.85 with levels of 20-30 ng/mL (95% CI, 0.56-1.28).
- 0.93 with levels < 20 ng/mL (95% CI, 0.50-1.74).
The test for treatment effect modification by baseline serum 25-OHD level was not significant (P for interaction = .83).
In addition, the rate of muscle symptoms was similar between participants randomized to vitamin D and placebo when researchers used a cutpoint to define low 25-OHD of < 30 ng/mL (27% vs. 30%) or < 20 ng/mL (33% vs. 35%).
“We didn’t find any evidence at all that the people who came into the study with low levels of vitamin D did better with the supplement in this case,” Dr. Hlatky said. “So that wasn’t the reason we didn’t see anything.”
Critics may suggest the trial didn’t use a high enough dose of vitamin D, but both Dr. Hlatky and Dr. Stone say that’s unlikely to be a factor in the results because 2,000 IU/d is a substantial dose and well above the recommended adult daily dose of 600-800 IU.
They caution that the substudy wasn’t prespecified, was smaller than the parent trial, and did not have a protocol in place to detail SAMS. They also can’t rule out the possibility that vitamin D may have an effect in patients who have confirmed intolerance to multiple statins, especially after adjustment for the statin type and dose.
“If you’re taking vitamin D to keep from having statin-associated muscle symptoms, this very carefully done substudy with the various caveats doesn’t support that and that’s not something I would give my patients,” Dr. Stone said.
“The most important thing from a negative study is that it allows you to focus your attention on things that may be much more productive rather than assuming that just giving everybody vitamin D will take care of the statin issue,” he added. “Maybe the answer is going to be somewhere else, and there’ll be a lot of people I’m sure who will offer their advice as what the answer is but, I would argue, we want to see more studies to pin it down. So people can get some science behind what they do to try to reduce statin-associated muscle symptoms.”
Paul D. Thompson, MD, chief of cardiology emeritus at Hartford (Conn.) Hospital, and a SAMS expert who was not involved with the research, said, “This is a useful publication, and it’s smart in that it took advantage of a study that was already done.”
He acknowledged being skeptical of a beneficial effect of vitamin D supplementation on SAMS, because some previous data have been retracted, but said that potential treatments are best tested in patients with confirmed statin myalgia, as was the case in his team’s negative trial of CoQ10 supplementation.
That said, the present “study was able to at least give some of the best evidence so far that vitamin D doesn’t do anything to improve symptoms,” Dr. Thompson said. “So maybe it will cut down on so many vitamin D levels [being measured] and use of vitamin D when you don’t really need it.”
The study was sponsored by the Hyperlipidemia Research Fund at Northwestern University. The VITAL trial was supported by grants from the National Institutes of Health, and Quest Diagnostics performed the laboratory measurements at no additional costs. Dr. Hlatky reports no relevant financial relationships. Dr. Stone reports a grant from the Hyperlipidemia Research Fund at Northwestern and honorarium for educational activity for Knowledge to Practice. Dr. Thompson is on the executive committee for a study examining bempedoic acid in patients with statin-associated muscle symptoms.
A version of this article first appeared on Medscape.com.
Vitamin D supplements do not prevent muscle symptoms in new statin users or affect the likelihood of discontinuing a statin due to muscle pain and discomfort, a substudy of the VITAL trial indicates.
Among more than 2,000 randomized participants, statin-associated muscle symptoms (SAMS) were reported by 31% assigned to vitamin D and 31% assigned to placebo.
The two groups were equally likely to stop taking a statin due to muscle symptoms, at 13%.
No significant difference was observed in SAMS (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.18) or statin discontinuations (OR, 1.04; 95% CI, 0.80-1.35) after adjustment for baseline variables and other characteristics, namely age, sex, and African-American race, previously found to be associated with SAMS in VITAL.
“We actually thought when we started out that maybe we were going to show something, that maybe it was going to be that the people who got the vitamin D were least likely to have a problem with a statin than all those who didn’t get vitamin D, but that is not what we showed,” senior author Neil J. Stone, MD, Northwestern University, Chicago, told this news organization.
He noted that patients in the clinic with low levels of vitamin D often have muscle pain and discomfort and that previous unblinded studies suggested vitamin D might benefit patients with SAMS and reduce statin intolerance.
As previously reported, the double-blind VITAL trial showed no difference in the primary prevention of cardiovascular disease or cancer at 5 years among 25,871 middle-aged adults randomized to vitamin D3 at 2000 IU/d or placebo, regardless of their baseline vitamin D level.
Unlike previous studies showing a benefit with vitamin D on SAMS, importantly, VITAL participants were unaware of whether they were taking vitamin D or placebo and were not expecting any help with their muscle symptoms, first author Mark A. Hlatky, MD, Stanford (Calif.) University, pointed out in an interview.
As to how many statin users turn to the popular supplement for SAMS, he said that number couldn’t be pinned down, despite a lengthy search. “But I think it’s very common, because up to half of people stop taking their statins within a year and many of these do so because of statin-associated muscle symptoms, and we found it in about 30% of people who have them. I have them myself and was motivated to study it because I thought this was an interesting question.”
The results were published online in JAMA Cardiology.
SAMS by baseline 25-OHD
The substudy included 2,083 patients who initiated statin therapy after randomization and were surveyed in early 2016 about their statin use and muscle symptoms.
Two-thirds, or 1,397 patients, had 25-hydroxy vitamin D (25-OHD) measured at baseline, with 47% having levels < 30 ng/mL and 13% levels < 20 ng/mL.
Serum 25-OHD levels were virtually identical in the two treatment groups (mean, 30.4 ng/mL; median, 30.0 ng/mL). The frequency of SAMS did not differ between those assigned to vitamin D or placebo (28% vs. 31%).
The odds ratios for the association with vitamin D on SAMS were:
- 0.86 in all respondents with 25-OHD measured (95% CI, 0.69-1.09).
- 0.87 in those with levels ≥ 30 ng/mL (95% CI, 0.64-1.19).
- 0.85 with levels of 20-30 ng/mL (95% CI, 0.56-1.28).
- 0.93 with levels < 20 ng/mL (95% CI, 0.50-1.74).
The test for treatment effect modification by baseline serum 25-OHD level was not significant (P for interaction = .83).
In addition, the rate of muscle symptoms was similar between participants randomized to vitamin D and placebo when researchers used a cutpoint to define low 25-OHD of < 30 ng/mL (27% vs. 30%) or < 20 ng/mL (33% vs. 35%).
“We didn’t find any evidence at all that the people who came into the study with low levels of vitamin D did better with the supplement in this case,” Dr. Hlatky said. “So that wasn’t the reason we didn’t see anything.”
Critics may suggest the trial didn’t use a high enough dose of vitamin D, but both Dr. Hlatky and Dr. Stone say that’s unlikely to be a factor in the results because 2,000 IU/d is a substantial dose and well above the recommended adult daily dose of 600-800 IU.
They caution that the substudy wasn’t prespecified, was smaller than the parent trial, and did not have a protocol in place to detail SAMS. They also can’t rule out the possibility that vitamin D may have an effect in patients who have confirmed intolerance to multiple statins, especially after adjustment for the statin type and dose.
“If you’re taking vitamin D to keep from having statin-associated muscle symptoms, this very carefully done substudy with the various caveats doesn’t support that and that’s not something I would give my patients,” Dr. Stone said.
“The most important thing from a negative study is that it allows you to focus your attention on things that may be much more productive rather than assuming that just giving everybody vitamin D will take care of the statin issue,” he added. “Maybe the answer is going to be somewhere else, and there’ll be a lot of people I’m sure who will offer their advice as what the answer is but, I would argue, we want to see more studies to pin it down. So people can get some science behind what they do to try to reduce statin-associated muscle symptoms.”
Paul D. Thompson, MD, chief of cardiology emeritus at Hartford (Conn.) Hospital, and a SAMS expert who was not involved with the research, said, “This is a useful publication, and it’s smart in that it took advantage of a study that was already done.”
He acknowledged being skeptical of a beneficial effect of vitamin D supplementation on SAMS, because some previous data have been retracted, but said that potential treatments are best tested in patients with confirmed statin myalgia, as was the case in his team’s negative trial of CoQ10 supplementation.
That said, the present “study was able to at least give some of the best evidence so far that vitamin D doesn’t do anything to improve symptoms,” Dr. Thompson said. “So maybe it will cut down on so many vitamin D levels [being measured] and use of vitamin D when you don’t really need it.”
The study was sponsored by the Hyperlipidemia Research Fund at Northwestern University. The VITAL trial was supported by grants from the National Institutes of Health, and Quest Diagnostics performed the laboratory measurements at no additional costs. Dr. Hlatky reports no relevant financial relationships. Dr. Stone reports a grant from the Hyperlipidemia Research Fund at Northwestern and honorarium for educational activity for Knowledge to Practice. Dr. Thompson is on the executive committee for a study examining bempedoic acid in patients with statin-associated muscle symptoms.
A version of this article first appeared on Medscape.com.
Vitamin D supplements do not prevent muscle symptoms in new statin users or affect the likelihood of discontinuing a statin due to muscle pain and discomfort, a substudy of the VITAL trial indicates.
Among more than 2,000 randomized participants, statin-associated muscle symptoms (SAMS) were reported by 31% assigned to vitamin D and 31% assigned to placebo.
The two groups were equally likely to stop taking a statin due to muscle symptoms, at 13%.
No significant difference was observed in SAMS (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.18) or statin discontinuations (OR, 1.04; 95% CI, 0.80-1.35) after adjustment for baseline variables and other characteristics, namely age, sex, and African-American race, previously found to be associated with SAMS in VITAL.
“We actually thought when we started out that maybe we were going to show something, that maybe it was going to be that the people who got the vitamin D were least likely to have a problem with a statin than all those who didn’t get vitamin D, but that is not what we showed,” senior author Neil J. Stone, MD, Northwestern University, Chicago, told this news organization.
He noted that patients in the clinic with low levels of vitamin D often have muscle pain and discomfort and that previous unblinded studies suggested vitamin D might benefit patients with SAMS and reduce statin intolerance.
As previously reported, the double-blind VITAL trial showed no difference in the primary prevention of cardiovascular disease or cancer at 5 years among 25,871 middle-aged adults randomized to vitamin D3 at 2000 IU/d or placebo, regardless of their baseline vitamin D level.
Unlike previous studies showing a benefit with vitamin D on SAMS, importantly, VITAL participants were unaware of whether they were taking vitamin D or placebo and were not expecting any help with their muscle symptoms, first author Mark A. Hlatky, MD, Stanford (Calif.) University, pointed out in an interview.
As to how many statin users turn to the popular supplement for SAMS, he said that number couldn’t be pinned down, despite a lengthy search. “But I think it’s very common, because up to half of people stop taking their statins within a year and many of these do so because of statin-associated muscle symptoms, and we found it in about 30% of people who have them. I have them myself and was motivated to study it because I thought this was an interesting question.”
The results were published online in JAMA Cardiology.
SAMS by baseline 25-OHD
The substudy included 2,083 patients who initiated statin therapy after randomization and were surveyed in early 2016 about their statin use and muscle symptoms.
Two-thirds, or 1,397 patients, had 25-hydroxy vitamin D (25-OHD) measured at baseline, with 47% having levels < 30 ng/mL and 13% levels < 20 ng/mL.
Serum 25-OHD levels were virtually identical in the two treatment groups (mean, 30.4 ng/mL; median, 30.0 ng/mL). The frequency of SAMS did not differ between those assigned to vitamin D or placebo (28% vs. 31%).
The odds ratios for the association with vitamin D on SAMS were:
- 0.86 in all respondents with 25-OHD measured (95% CI, 0.69-1.09).
- 0.87 in those with levels ≥ 30 ng/mL (95% CI, 0.64-1.19).
- 0.85 with levels of 20-30 ng/mL (95% CI, 0.56-1.28).
- 0.93 with levels < 20 ng/mL (95% CI, 0.50-1.74).
The test for treatment effect modification by baseline serum 25-OHD level was not significant (P for interaction = .83).
In addition, the rate of muscle symptoms was similar between participants randomized to vitamin D and placebo when researchers used a cutpoint to define low 25-OHD of < 30 ng/mL (27% vs. 30%) or < 20 ng/mL (33% vs. 35%).
“We didn’t find any evidence at all that the people who came into the study with low levels of vitamin D did better with the supplement in this case,” Dr. Hlatky said. “So that wasn’t the reason we didn’t see anything.”
Critics may suggest the trial didn’t use a high enough dose of vitamin D, but both Dr. Hlatky and Dr. Stone say that’s unlikely to be a factor in the results because 2,000 IU/d is a substantial dose and well above the recommended adult daily dose of 600-800 IU.
They caution that the substudy wasn’t prespecified, was smaller than the parent trial, and did not have a protocol in place to detail SAMS. They also can’t rule out the possibility that vitamin D may have an effect in patients who have confirmed intolerance to multiple statins, especially after adjustment for the statin type and dose.
“If you’re taking vitamin D to keep from having statin-associated muscle symptoms, this very carefully done substudy with the various caveats doesn’t support that and that’s not something I would give my patients,” Dr. Stone said.
“The most important thing from a negative study is that it allows you to focus your attention on things that may be much more productive rather than assuming that just giving everybody vitamin D will take care of the statin issue,” he added. “Maybe the answer is going to be somewhere else, and there’ll be a lot of people I’m sure who will offer their advice as what the answer is but, I would argue, we want to see more studies to pin it down. So people can get some science behind what they do to try to reduce statin-associated muscle symptoms.”
Paul D. Thompson, MD, chief of cardiology emeritus at Hartford (Conn.) Hospital, and a SAMS expert who was not involved with the research, said, “This is a useful publication, and it’s smart in that it took advantage of a study that was already done.”
He acknowledged being skeptical of a beneficial effect of vitamin D supplementation on SAMS, because some previous data have been retracted, but said that potential treatments are best tested in patients with confirmed statin myalgia, as was the case in his team’s negative trial of CoQ10 supplementation.
That said, the present “study was able to at least give some of the best evidence so far that vitamin D doesn’t do anything to improve symptoms,” Dr. Thompson said. “So maybe it will cut down on so many vitamin D levels [being measured] and use of vitamin D when you don’t really need it.”
The study was sponsored by the Hyperlipidemia Research Fund at Northwestern University. The VITAL trial was supported by grants from the National Institutes of Health, and Quest Diagnostics performed the laboratory measurements at no additional costs. Dr. Hlatky reports no relevant financial relationships. Dr. Stone reports a grant from the Hyperlipidemia Research Fund at Northwestern and honorarium for educational activity for Knowledge to Practice. Dr. Thompson is on the executive committee for a study examining bempedoic acid in patients with statin-associated muscle symptoms.
A version of this article first appeared on Medscape.com.
Transgender patients on hormone therapy require monitoring
PAU, France – Transgender patients on hormone therapy have an increased mortality risk and so must be closely monitored, especially in terms of cardiovascular health and oncology, reported Marie D’Assigny, MD, of the department of endocrinology, diabetes, and dietetics at Poitiers (France) University Hospital, at the Infogyn 2022 conference. Because transgender women (those assigned male at birth who have assumed a female gender identity) are at risk of breast cancer, they should also be recommended for breast cancer screening.
Transgender men and women, especially transgender women, “should be deemed high-risk cardiovascular patients, or even very high risk in some cases,” said Dr. D’Assigny. This means that they should be considered candidates for cholesterol-lowering medication earlier than their cisgender counterparts, and a target LDL cholesterol of less than 0.70 g/L (70 mg/dL) should be sought. Likewise, blood pressure must be strictly monitored, especially because it tends to rise when on hormone therapy.
Feminizing hormone therapy requires chemical castration with the use of anti-androgen drugs to achieve a blood testosterone level less than 0.5 ng/mL (1.73 nmol/L). Low-dose cyproterone acetate (< 25 to 50 mg/day) is usually used. Treatment is stopped if a patient undergoes an orchidectomy. For feminizing hormone therapy, administration of 17beta-estradiol transcutaneously (patch or gel) is recommended, because it is associated with a lower risk of thromboembolism than oral administration.
Masculinizing hormone therapy is based on administration of progestogens, then testosterone in the form of an injection (mostly testosterone enanthate via intramuscular injection every 10 days) or percutaneously (gel or patch). There are few contraindications, and treatment is generally well tolerated.
High mortality rate
A recent retrospective study highlighted the mortality and risk factors for death in transgender men and women receiving hormone therapy. More than 4,500 people, mostly male to female transgender women, were enrolled in this study, which was conducted over a 47-year period (1972-2018) at a specialist clinic at Amsterdam UMC.
Over the course of the study, the mortality rate in transgender men and women was twice that of the general population. The death rate was 10.8% in transgender women vs. 2.7% in transgender men, after a follow-up of 40,232 person-years and 17,285 person-years, respectively. In transgender women, mortality was nearly three times that of cisgender women in the general population.
Over the nearly 5 decades of study, there was no improvement in the mortality rate, even over the last 10 years when transgender issues started to be more recognized. The mortality trends are markedly distinct over the years from those observed in the cisgender population, and this is especially true for transgender women compared to transgender men. “Much is still to be done,” said Dr. D’Assigny.
According to the study, cause-specific mortality in transgender women was high for cardiovascular disease and lung cancer, possibly because of a higher smoking rate in this population. HIV-related disease and suicide remained very high in both transgender men and women.
People with gender dysphoria who do not receive treatment for gender reassignment have a suicide rate of 40%, reported François-Xavier Madec, MD, of Foch Hospital in Suresnes, France, at a previous presentation. For transgender men and women who receive care, this rate is lowered to 15%, which is still significantly higher than the rate of 1.6% observed in the general population.
“These causes of death don’t give any indication as to a specific effect of hormone treatment but show that monitoring and, if necessary, treatment of comorbidities and lifestyle-related factors are important in managing transgender patients,” said the study authors.
“Strengthening social acceptance and treating cardiovascular risk factors could also help to reduce mortality in transgender men and women,” they added.
Screening for osteoporosis
In addition to receiving cardiovascular risk factor assessment and monitoring, transgender men and women on hormone therapy should also undergo bone density testing “when risk factors for osteoporosis are present, especially in patients stopping hormone therapy after a gonadectomy,” said Dr. D’Assigny.
Calcium and vitamin D supplements are also recommended for all patients after a gonadectomy, especially in transgender men on testosterone. Osteoporosis screening is recommended for transgender men 10 years after starting treatment with testosterone, then every 10 years.
There is also the risk for breast cancer in transgender women, although the risk is lower than in cisgender women. This risk was highlighted in another study of more than 2,260 transgender women that was carried out by a team at Amsterdam UMC.
A total of 18 cases of breast cancer (15 invasive) were diagnosed after a median 18 years of hormone treatment. This represents an incidence of breast cancer that is 46 times higher than that expected in cisgender men of the same age but 3 times lower than in cisgender women.
The authors noted that “the risk of breast cancer in transgender women increases during a relatively short duration of hormone treatment,” going on to say that “these results suggest that breast cancer screening recommendations are relevant for transgender men and women on hormone therapy.”
Poorly attended screening
All of this means that transgender women older than age 50 years, as well as transgender men who have not had a mastectomy, should be offered a mammogram screening, taking into account the possible presence of implants in the former. Transgender women are also at risk for prostate cancer. Monitoring is personalized according to the individual risk of prostate disease, as it is for cisgender men.
There is no consensus on the monitoring of transgender men on hormone therapy for uterine cancer. Yet there is a risk. “Testosterone causes thinning of the endometrium, which may lead to dysplasia,” said Dr. D’Assigny. A physical examination once a year or a pelvic ultrasound scan every 2 years should form the basis of endometrial and ovarian appearance monitoring.
Transgender women are also at risk for prostate cancer. However, they are less likely to attend a prostate cancer screening test, said Dr. D’Assigny, which means “we need to raise awareness of their benefit in advance.” Vaginal swabs for transgender men and mammograms in transgender women “are resented, on both a physical and emotional level.” As a result, delays in diagnosis are common in transgender men and women.
Globally, access to care is still difficult for transgender patients because they don’t always receive appropriate gynecological monitoring, through fear of judgment or discrimination. Many transgender men and women are reluctant to see a gynecologist, even though they are at risk of gynecological cancers, as well as unwanted pregnancies in transgender men who have not undergone a hysterectomy.
In a demonstration of the collective desire to improve patient care for the transgender community, a literature review was recently published by a French team that analyzed gynecological monitoring methods in transgender patients. In September, the French National Authority for Health also issued a guidance memorandum on the transgender transition pathway, pending new recommendations scheduled for 2023.
A version of this article first appeared on Medscape.com.
This article was translated from the Medscape French edition.
PAU, France – Transgender patients on hormone therapy have an increased mortality risk and so must be closely monitored, especially in terms of cardiovascular health and oncology, reported Marie D’Assigny, MD, of the department of endocrinology, diabetes, and dietetics at Poitiers (France) University Hospital, at the Infogyn 2022 conference. Because transgender women (those assigned male at birth who have assumed a female gender identity) are at risk of breast cancer, they should also be recommended for breast cancer screening.
Transgender men and women, especially transgender women, “should be deemed high-risk cardiovascular patients, or even very high risk in some cases,” said Dr. D’Assigny. This means that they should be considered candidates for cholesterol-lowering medication earlier than their cisgender counterparts, and a target LDL cholesterol of less than 0.70 g/L (70 mg/dL) should be sought. Likewise, blood pressure must be strictly monitored, especially because it tends to rise when on hormone therapy.
Feminizing hormone therapy requires chemical castration with the use of anti-androgen drugs to achieve a blood testosterone level less than 0.5 ng/mL (1.73 nmol/L). Low-dose cyproterone acetate (< 25 to 50 mg/day) is usually used. Treatment is stopped if a patient undergoes an orchidectomy. For feminizing hormone therapy, administration of 17beta-estradiol transcutaneously (patch or gel) is recommended, because it is associated with a lower risk of thromboembolism than oral administration.
Masculinizing hormone therapy is based on administration of progestogens, then testosterone in the form of an injection (mostly testosterone enanthate via intramuscular injection every 10 days) or percutaneously (gel or patch). There are few contraindications, and treatment is generally well tolerated.
High mortality rate
A recent retrospective study highlighted the mortality and risk factors for death in transgender men and women receiving hormone therapy. More than 4,500 people, mostly male to female transgender women, were enrolled in this study, which was conducted over a 47-year period (1972-2018) at a specialist clinic at Amsterdam UMC.
Over the course of the study, the mortality rate in transgender men and women was twice that of the general population. The death rate was 10.8% in transgender women vs. 2.7% in transgender men, after a follow-up of 40,232 person-years and 17,285 person-years, respectively. In transgender women, mortality was nearly three times that of cisgender women in the general population.
Over the nearly 5 decades of study, there was no improvement in the mortality rate, even over the last 10 years when transgender issues started to be more recognized. The mortality trends are markedly distinct over the years from those observed in the cisgender population, and this is especially true for transgender women compared to transgender men. “Much is still to be done,” said Dr. D’Assigny.
According to the study, cause-specific mortality in transgender women was high for cardiovascular disease and lung cancer, possibly because of a higher smoking rate in this population. HIV-related disease and suicide remained very high in both transgender men and women.
People with gender dysphoria who do not receive treatment for gender reassignment have a suicide rate of 40%, reported François-Xavier Madec, MD, of Foch Hospital in Suresnes, France, at a previous presentation. For transgender men and women who receive care, this rate is lowered to 15%, which is still significantly higher than the rate of 1.6% observed in the general population.
“These causes of death don’t give any indication as to a specific effect of hormone treatment but show that monitoring and, if necessary, treatment of comorbidities and lifestyle-related factors are important in managing transgender patients,” said the study authors.
“Strengthening social acceptance and treating cardiovascular risk factors could also help to reduce mortality in transgender men and women,” they added.
Screening for osteoporosis
In addition to receiving cardiovascular risk factor assessment and monitoring, transgender men and women on hormone therapy should also undergo bone density testing “when risk factors for osteoporosis are present, especially in patients stopping hormone therapy after a gonadectomy,” said Dr. D’Assigny.
Calcium and vitamin D supplements are also recommended for all patients after a gonadectomy, especially in transgender men on testosterone. Osteoporosis screening is recommended for transgender men 10 years after starting treatment with testosterone, then every 10 years.
There is also the risk for breast cancer in transgender women, although the risk is lower than in cisgender women. This risk was highlighted in another study of more than 2,260 transgender women that was carried out by a team at Amsterdam UMC.
A total of 18 cases of breast cancer (15 invasive) were diagnosed after a median 18 years of hormone treatment. This represents an incidence of breast cancer that is 46 times higher than that expected in cisgender men of the same age but 3 times lower than in cisgender women.
The authors noted that “the risk of breast cancer in transgender women increases during a relatively short duration of hormone treatment,” going on to say that “these results suggest that breast cancer screening recommendations are relevant for transgender men and women on hormone therapy.”
Poorly attended screening
All of this means that transgender women older than age 50 years, as well as transgender men who have not had a mastectomy, should be offered a mammogram screening, taking into account the possible presence of implants in the former. Transgender women are also at risk for prostate cancer. Monitoring is personalized according to the individual risk of prostate disease, as it is for cisgender men.
There is no consensus on the monitoring of transgender men on hormone therapy for uterine cancer. Yet there is a risk. “Testosterone causes thinning of the endometrium, which may lead to dysplasia,” said Dr. D’Assigny. A physical examination once a year or a pelvic ultrasound scan every 2 years should form the basis of endometrial and ovarian appearance monitoring.
Transgender women are also at risk for prostate cancer. However, they are less likely to attend a prostate cancer screening test, said Dr. D’Assigny, which means “we need to raise awareness of their benefit in advance.” Vaginal swabs for transgender men and mammograms in transgender women “are resented, on both a physical and emotional level.” As a result, delays in diagnosis are common in transgender men and women.
Globally, access to care is still difficult for transgender patients because they don’t always receive appropriate gynecological monitoring, through fear of judgment or discrimination. Many transgender men and women are reluctant to see a gynecologist, even though they are at risk of gynecological cancers, as well as unwanted pregnancies in transgender men who have not undergone a hysterectomy.
In a demonstration of the collective desire to improve patient care for the transgender community, a literature review was recently published by a French team that analyzed gynecological monitoring methods in transgender patients. In September, the French National Authority for Health also issued a guidance memorandum on the transgender transition pathway, pending new recommendations scheduled for 2023.
A version of this article first appeared on Medscape.com.
This article was translated from the Medscape French edition.
PAU, France – Transgender patients on hormone therapy have an increased mortality risk and so must be closely monitored, especially in terms of cardiovascular health and oncology, reported Marie D’Assigny, MD, of the department of endocrinology, diabetes, and dietetics at Poitiers (France) University Hospital, at the Infogyn 2022 conference. Because transgender women (those assigned male at birth who have assumed a female gender identity) are at risk of breast cancer, they should also be recommended for breast cancer screening.
Transgender men and women, especially transgender women, “should be deemed high-risk cardiovascular patients, or even very high risk in some cases,” said Dr. D’Assigny. This means that they should be considered candidates for cholesterol-lowering medication earlier than their cisgender counterparts, and a target LDL cholesterol of less than 0.70 g/L (70 mg/dL) should be sought. Likewise, blood pressure must be strictly monitored, especially because it tends to rise when on hormone therapy.
Feminizing hormone therapy requires chemical castration with the use of anti-androgen drugs to achieve a blood testosterone level less than 0.5 ng/mL (1.73 nmol/L). Low-dose cyproterone acetate (< 25 to 50 mg/day) is usually used. Treatment is stopped if a patient undergoes an orchidectomy. For feminizing hormone therapy, administration of 17beta-estradiol transcutaneously (patch or gel) is recommended, because it is associated with a lower risk of thromboembolism than oral administration.
Masculinizing hormone therapy is based on administration of progestogens, then testosterone in the form of an injection (mostly testosterone enanthate via intramuscular injection every 10 days) or percutaneously (gel or patch). There are few contraindications, and treatment is generally well tolerated.
High mortality rate
A recent retrospective study highlighted the mortality and risk factors for death in transgender men and women receiving hormone therapy. More than 4,500 people, mostly male to female transgender women, were enrolled in this study, which was conducted over a 47-year period (1972-2018) at a specialist clinic at Amsterdam UMC.
Over the course of the study, the mortality rate in transgender men and women was twice that of the general population. The death rate was 10.8% in transgender women vs. 2.7% in transgender men, after a follow-up of 40,232 person-years and 17,285 person-years, respectively. In transgender women, mortality was nearly three times that of cisgender women in the general population.
Over the nearly 5 decades of study, there was no improvement in the mortality rate, even over the last 10 years when transgender issues started to be more recognized. The mortality trends are markedly distinct over the years from those observed in the cisgender population, and this is especially true for transgender women compared to transgender men. “Much is still to be done,” said Dr. D’Assigny.
According to the study, cause-specific mortality in transgender women was high for cardiovascular disease and lung cancer, possibly because of a higher smoking rate in this population. HIV-related disease and suicide remained very high in both transgender men and women.
People with gender dysphoria who do not receive treatment for gender reassignment have a suicide rate of 40%, reported François-Xavier Madec, MD, of Foch Hospital in Suresnes, France, at a previous presentation. For transgender men and women who receive care, this rate is lowered to 15%, which is still significantly higher than the rate of 1.6% observed in the general population.
“These causes of death don’t give any indication as to a specific effect of hormone treatment but show that monitoring and, if necessary, treatment of comorbidities and lifestyle-related factors are important in managing transgender patients,” said the study authors.
“Strengthening social acceptance and treating cardiovascular risk factors could also help to reduce mortality in transgender men and women,” they added.
Screening for osteoporosis
In addition to receiving cardiovascular risk factor assessment and monitoring, transgender men and women on hormone therapy should also undergo bone density testing “when risk factors for osteoporosis are present, especially in patients stopping hormone therapy after a gonadectomy,” said Dr. D’Assigny.
Calcium and vitamin D supplements are also recommended for all patients after a gonadectomy, especially in transgender men on testosterone. Osteoporosis screening is recommended for transgender men 10 years after starting treatment with testosterone, then every 10 years.
There is also the risk for breast cancer in transgender women, although the risk is lower than in cisgender women. This risk was highlighted in another study of more than 2,260 transgender women that was carried out by a team at Amsterdam UMC.
A total of 18 cases of breast cancer (15 invasive) were diagnosed after a median 18 years of hormone treatment. This represents an incidence of breast cancer that is 46 times higher than that expected in cisgender men of the same age but 3 times lower than in cisgender women.
The authors noted that “the risk of breast cancer in transgender women increases during a relatively short duration of hormone treatment,” going on to say that “these results suggest that breast cancer screening recommendations are relevant for transgender men and women on hormone therapy.”
Poorly attended screening
All of this means that transgender women older than age 50 years, as well as transgender men who have not had a mastectomy, should be offered a mammogram screening, taking into account the possible presence of implants in the former. Transgender women are also at risk for prostate cancer. Monitoring is personalized according to the individual risk of prostate disease, as it is for cisgender men.
There is no consensus on the monitoring of transgender men on hormone therapy for uterine cancer. Yet there is a risk. “Testosterone causes thinning of the endometrium, which may lead to dysplasia,” said Dr. D’Assigny. A physical examination once a year or a pelvic ultrasound scan every 2 years should form the basis of endometrial and ovarian appearance monitoring.
Transgender women are also at risk for prostate cancer. However, they are less likely to attend a prostate cancer screening test, said Dr. D’Assigny, which means “we need to raise awareness of their benefit in advance.” Vaginal swabs for transgender men and mammograms in transgender women “are resented, on both a physical and emotional level.” As a result, delays in diagnosis are common in transgender men and women.
Globally, access to care is still difficult for transgender patients because they don’t always receive appropriate gynecological monitoring, through fear of judgment or discrimination. Many transgender men and women are reluctant to see a gynecologist, even though they are at risk of gynecological cancers, as well as unwanted pregnancies in transgender men who have not undergone a hysterectomy.
In a demonstration of the collective desire to improve patient care for the transgender community, a literature review was recently published by a French team that analyzed gynecological monitoring methods in transgender patients. In September, the French National Authority for Health also issued a guidance memorandum on the transgender transition pathway, pending new recommendations scheduled for 2023.
A version of this article first appeared on Medscape.com.
This article was translated from the Medscape French edition.
Jump starting thankfulness
One night, at the beginning of Thanksgiving week, my son called from his place across town. His car was having trouble starting, so I went to see what was up.
I got to his place to find his car wouldn’t start, even though the battery was only a few months old. I used my car to jump his, left him mine, and headed back. My plan was to leave it at our usual repair place and walk home.
Easier said than done.
I’d just gotten on the 101, the main loop freeway for the Phoenix metro area, when his car completely died. The lights flickered, the gauges stopped working, and then the engine cut out. Mercifully I was able to pull over into the right emergency lane as it did so. I was nowhere near an exit.
Not even the emergency flashers worked. It was dark. I was on a major freeway. I couldn’t make myself visible. Cars and trucks were whizzing by 2-3 feet to my left, and I was hoping they’d see me.
I called AAA and explained the situation. They were sending a tow truck, but it could take up to another 3 hours. I sent some quick texts to family to let them know what was up. I called the AZ highway patrol to let them know my predicament, in case they wanted to come put a flare or two behind me (they didn’t).
And then I settled in. Seatbelt on, staring at the road in front of me ... and had nothing to do.
When was the last time you had absolutely nothing to do?
It’s pretty rare these days. I mean, we all have breaks in the action, so we watch a cute animal video, or play a round of Wordle, or whatever.
But I had none of that. No books, iPad, or computer. Sure, I had my phone, but it was less than 50% charged with no way to charge it, and so I wanted to conserve that in case I needed it.
I don’t think I’ve ever had a moment like this since I began carrying a phone in 1998. There was, literally, nothing to do but wait. I couldn’t even try to nod off with the seat unadjustable and cars whizzing by.
So my mind wandered, and I thought. I turned over office cases. I went through year-end finances. I thought about my current predicament. I stared endlessly at the road ahead and cars passing me.
At some point I began to realize that I’m actually pretty lucky, and that nothing was nearly as bad as it had seemed earlier in the day. As the initial adrenaline rush drained out of me I calmed down and the things I’d been worrying about that afternoon seemed workable.
The tow truck pulled in front of me, ending my reverie. Mercifully, it had only taken them an hour. I was home 45 minutes later.
I was thankful to be home and I was thankful that nothing more serious had happened in a potentially bad situation.
And, somewhere in there,
In today’s world of endless screens and texts and calls and notifications, it’s easy to lose track of that.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
One night, at the beginning of Thanksgiving week, my son called from his place across town. His car was having trouble starting, so I went to see what was up.
I got to his place to find his car wouldn’t start, even though the battery was only a few months old. I used my car to jump his, left him mine, and headed back. My plan was to leave it at our usual repair place and walk home.
Easier said than done.
I’d just gotten on the 101, the main loop freeway for the Phoenix metro area, when his car completely died. The lights flickered, the gauges stopped working, and then the engine cut out. Mercifully I was able to pull over into the right emergency lane as it did so. I was nowhere near an exit.
Not even the emergency flashers worked. It was dark. I was on a major freeway. I couldn’t make myself visible. Cars and trucks were whizzing by 2-3 feet to my left, and I was hoping they’d see me.
I called AAA and explained the situation. They were sending a tow truck, but it could take up to another 3 hours. I sent some quick texts to family to let them know what was up. I called the AZ highway patrol to let them know my predicament, in case they wanted to come put a flare or two behind me (they didn’t).
And then I settled in. Seatbelt on, staring at the road in front of me ... and had nothing to do.
When was the last time you had absolutely nothing to do?
It’s pretty rare these days. I mean, we all have breaks in the action, so we watch a cute animal video, or play a round of Wordle, or whatever.
But I had none of that. No books, iPad, or computer. Sure, I had my phone, but it was less than 50% charged with no way to charge it, and so I wanted to conserve that in case I needed it.
I don’t think I’ve ever had a moment like this since I began carrying a phone in 1998. There was, literally, nothing to do but wait. I couldn’t even try to nod off with the seat unadjustable and cars whizzing by.
So my mind wandered, and I thought. I turned over office cases. I went through year-end finances. I thought about my current predicament. I stared endlessly at the road ahead and cars passing me.
At some point I began to realize that I’m actually pretty lucky, and that nothing was nearly as bad as it had seemed earlier in the day. As the initial adrenaline rush drained out of me I calmed down and the things I’d been worrying about that afternoon seemed workable.
The tow truck pulled in front of me, ending my reverie. Mercifully, it had only taken them an hour. I was home 45 minutes later.
I was thankful to be home and I was thankful that nothing more serious had happened in a potentially bad situation.
And, somewhere in there,
In today’s world of endless screens and texts and calls and notifications, it’s easy to lose track of that.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
One night, at the beginning of Thanksgiving week, my son called from his place across town. His car was having trouble starting, so I went to see what was up.
I got to his place to find his car wouldn’t start, even though the battery was only a few months old. I used my car to jump his, left him mine, and headed back. My plan was to leave it at our usual repair place and walk home.
Easier said than done.
I’d just gotten on the 101, the main loop freeway for the Phoenix metro area, when his car completely died. The lights flickered, the gauges stopped working, and then the engine cut out. Mercifully I was able to pull over into the right emergency lane as it did so. I was nowhere near an exit.
Not even the emergency flashers worked. It was dark. I was on a major freeway. I couldn’t make myself visible. Cars and trucks were whizzing by 2-3 feet to my left, and I was hoping they’d see me.
I called AAA and explained the situation. They were sending a tow truck, but it could take up to another 3 hours. I sent some quick texts to family to let them know what was up. I called the AZ highway patrol to let them know my predicament, in case they wanted to come put a flare or two behind me (they didn’t).
And then I settled in. Seatbelt on, staring at the road in front of me ... and had nothing to do.
When was the last time you had absolutely nothing to do?
It’s pretty rare these days. I mean, we all have breaks in the action, so we watch a cute animal video, or play a round of Wordle, or whatever.
But I had none of that. No books, iPad, or computer. Sure, I had my phone, but it was less than 50% charged with no way to charge it, and so I wanted to conserve that in case I needed it.
I don’t think I’ve ever had a moment like this since I began carrying a phone in 1998. There was, literally, nothing to do but wait. I couldn’t even try to nod off with the seat unadjustable and cars whizzing by.
So my mind wandered, and I thought. I turned over office cases. I went through year-end finances. I thought about my current predicament. I stared endlessly at the road ahead and cars passing me.
At some point I began to realize that I’m actually pretty lucky, and that nothing was nearly as bad as it had seemed earlier in the day. As the initial adrenaline rush drained out of me I calmed down and the things I’d been worrying about that afternoon seemed workable.
The tow truck pulled in front of me, ending my reverie. Mercifully, it had only taken them an hour. I was home 45 minutes later.
I was thankful to be home and I was thankful that nothing more serious had happened in a potentially bad situation.
And, somewhere in there,
In today’s world of endless screens and texts and calls and notifications, it’s easy to lose track of that.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Immunotherapy may be path forward in HPV oropharyngeal cancer
In human papillomavirus (HPV)-positive, locally advanced oropharyngeal squamous cell carcinoma, an immune checkpoint blockade regimen combined with radiotherapy led to good survival with a reduction in radiation exposure.
First-line therapy for HPV-positive oropharynx cancer is generally high-dose cisplatin combined with high-dose radiotherapy, but this regimen is associated with significant acute and long-term toxicity.
In previous studies among patients with recurrent or metastatic squamous cell carcinoma, nivolumab (Opdiva, Bristol Myers Squibb) improved survival when combined with platinum-based chemotherapy, and pembrolizumab (Keytruda, Merck) improved survival in recurrent disease compared with chemotherapy plus cetuximab.
Those precedents predicted success for HPV-positive oropharynx cancer, according to Maura Gillison, MD, PhD, who presented the results at a press briefing held in November in advance of the Society for Immunotherapy of Cancer’s 37th Annual Meeting. “Given that HPV-positive oropharynx cancers are characterized by an inflamed tumor microenvironment and HPV oncoproteins are omnipresent, required for cancer survival, and are ideal tumor-specific antigens – we hypothesized that induction and concurrent CTLA-4 and PD-1 immune checkpoint blockade, followed by volume- and dose-adapted IMRT (intensity-modulated radiotherapy), would be an effective alternative to the current standard of care,” said Dr. Gillison, who is a professor of medicine at the University of Texas MD Anderson Cancer Center, Houston.
, according to Robert Ferris, MD, PhD, who moderated the press briefing and was lead author of the nivolumab in metastatic squamous cell carcinoma study. He added that recent trial data suggest this approach should be more effective and create more durable responses.
The new data support the approach. “The trial provides compelling data to support a new approach for treating newly diagnosed HPV-positive head and neck cancers. Our goal is to treat this cancer with immunotherapy alone. The results of this trial make me optimistic that this will be achievable,” Dr. Gillison said.
The study details
The researchers conducted a phase 2 clinical trial, enrolling 35 patients with newly diagnosed HPV-positive oropharynx cancer who were positive for PD-L1 expression.
Patients received 1 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) and 3 mg/kg nivolumab over a 6-week cycle, followed by a second cycle that was accompanied by 40-44 Gy radiotherapy for patients with a complete response in their primary tumor, and a boost to 50-66 based on postinduction treatment volume. The protocol reduced dose to the neck from 52 to 36 Gy. The radiation was delivered to only one nodal echelon beyond the involved node. Standard care delivers radiotherapy to essentially the entire neck, Dr. Gillison said.
Grade 3 or higher adverse events occurred in 66% of patients, the majority of which were attributable to radiotherapy. The complete response rate was 94% at 6 months as assessed by PET scan, and 2-year progression-free survival was 86%. After a median follow-up of 14.9 months, all patients were alive and cancer-free.
Overall response rate was 14% following induction, but 96% showed a histologic treatment effect. Tumor viability was less than 5% in 48% of patients, and a molecular complete response was observed in 30% as measured by plasma cell-free HPV. Patients received 36% less radiation than typical of standard of care, and the dose to critical areas was reduced by 50%.
At the press conference, Dr. Ferris asked Dr. Gillison whether the researchers observed a spike in cell-free HPV DNA before the decline occurred, suggesting evidence of tumor death and DNA release.
“We did see in a remarkable number of patients within 2 weeks of the first dose, a very strong peak in the cell-free HPV DNA, followed by a rapid decline. In those patients who still have viable tumor at the end of induction immunotherapy, we saw a second robust peak in cell-free HPV DNA at the start of radiation, with rapid clearance. So that gave us confidence that (among) those patients who had cell-free HPV clearance by the end of induction, followed by no further detection through radiation, that it’s an excellent surrogate for tumor control,” Dr. Gillison said.
Dr. Gillison has financial relationships with Eisai, Exilixis, Caladrius, iTeos, Istari, Seagen, Sensei, Bicara, Mirati, Coherus, Debiopharm, Kura, Shattuck, Nektar, Ipsen, EMD Serono, Gilead, LXS, BioNTech, Merck, Bristol Myers Squibb, Bayer, Roche, Genocea, NewLink Genetics, Aspyrian, TRM Oncology, Amgen, AstraZeneca, Celgene, and Agenus. Dr. Ferris has financial relationships with Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, and Celgene.
In human papillomavirus (HPV)-positive, locally advanced oropharyngeal squamous cell carcinoma, an immune checkpoint blockade regimen combined with radiotherapy led to good survival with a reduction in radiation exposure.
First-line therapy for HPV-positive oropharynx cancer is generally high-dose cisplatin combined with high-dose radiotherapy, but this regimen is associated with significant acute and long-term toxicity.
In previous studies among patients with recurrent or metastatic squamous cell carcinoma, nivolumab (Opdiva, Bristol Myers Squibb) improved survival when combined with platinum-based chemotherapy, and pembrolizumab (Keytruda, Merck) improved survival in recurrent disease compared with chemotherapy plus cetuximab.
Those precedents predicted success for HPV-positive oropharynx cancer, according to Maura Gillison, MD, PhD, who presented the results at a press briefing held in November in advance of the Society for Immunotherapy of Cancer’s 37th Annual Meeting. “Given that HPV-positive oropharynx cancers are characterized by an inflamed tumor microenvironment and HPV oncoproteins are omnipresent, required for cancer survival, and are ideal tumor-specific antigens – we hypothesized that induction and concurrent CTLA-4 and PD-1 immune checkpoint blockade, followed by volume- and dose-adapted IMRT (intensity-modulated radiotherapy), would be an effective alternative to the current standard of care,” said Dr. Gillison, who is a professor of medicine at the University of Texas MD Anderson Cancer Center, Houston.
, according to Robert Ferris, MD, PhD, who moderated the press briefing and was lead author of the nivolumab in metastatic squamous cell carcinoma study. He added that recent trial data suggest this approach should be more effective and create more durable responses.
The new data support the approach. “The trial provides compelling data to support a new approach for treating newly diagnosed HPV-positive head and neck cancers. Our goal is to treat this cancer with immunotherapy alone. The results of this trial make me optimistic that this will be achievable,” Dr. Gillison said.
The study details
The researchers conducted a phase 2 clinical trial, enrolling 35 patients with newly diagnosed HPV-positive oropharynx cancer who were positive for PD-L1 expression.
Patients received 1 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) and 3 mg/kg nivolumab over a 6-week cycle, followed by a second cycle that was accompanied by 40-44 Gy radiotherapy for patients with a complete response in their primary tumor, and a boost to 50-66 based on postinduction treatment volume. The protocol reduced dose to the neck from 52 to 36 Gy. The radiation was delivered to only one nodal echelon beyond the involved node. Standard care delivers radiotherapy to essentially the entire neck, Dr. Gillison said.
Grade 3 or higher adverse events occurred in 66% of patients, the majority of which were attributable to radiotherapy. The complete response rate was 94% at 6 months as assessed by PET scan, and 2-year progression-free survival was 86%. After a median follow-up of 14.9 months, all patients were alive and cancer-free.
Overall response rate was 14% following induction, but 96% showed a histologic treatment effect. Tumor viability was less than 5% in 48% of patients, and a molecular complete response was observed in 30% as measured by plasma cell-free HPV. Patients received 36% less radiation than typical of standard of care, and the dose to critical areas was reduced by 50%.
At the press conference, Dr. Ferris asked Dr. Gillison whether the researchers observed a spike in cell-free HPV DNA before the decline occurred, suggesting evidence of tumor death and DNA release.
“We did see in a remarkable number of patients within 2 weeks of the first dose, a very strong peak in the cell-free HPV DNA, followed by a rapid decline. In those patients who still have viable tumor at the end of induction immunotherapy, we saw a second robust peak in cell-free HPV DNA at the start of radiation, with rapid clearance. So that gave us confidence that (among) those patients who had cell-free HPV clearance by the end of induction, followed by no further detection through radiation, that it’s an excellent surrogate for tumor control,” Dr. Gillison said.
Dr. Gillison has financial relationships with Eisai, Exilixis, Caladrius, iTeos, Istari, Seagen, Sensei, Bicara, Mirati, Coherus, Debiopharm, Kura, Shattuck, Nektar, Ipsen, EMD Serono, Gilead, LXS, BioNTech, Merck, Bristol Myers Squibb, Bayer, Roche, Genocea, NewLink Genetics, Aspyrian, TRM Oncology, Amgen, AstraZeneca, Celgene, and Agenus. Dr. Ferris has financial relationships with Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, and Celgene.
In human papillomavirus (HPV)-positive, locally advanced oropharyngeal squamous cell carcinoma, an immune checkpoint blockade regimen combined with radiotherapy led to good survival with a reduction in radiation exposure.
First-line therapy for HPV-positive oropharynx cancer is generally high-dose cisplatin combined with high-dose radiotherapy, but this regimen is associated with significant acute and long-term toxicity.
In previous studies among patients with recurrent or metastatic squamous cell carcinoma, nivolumab (Opdiva, Bristol Myers Squibb) improved survival when combined with platinum-based chemotherapy, and pembrolizumab (Keytruda, Merck) improved survival in recurrent disease compared with chemotherapy plus cetuximab.
Those precedents predicted success for HPV-positive oropharynx cancer, according to Maura Gillison, MD, PhD, who presented the results at a press briefing held in November in advance of the Society for Immunotherapy of Cancer’s 37th Annual Meeting. “Given that HPV-positive oropharynx cancers are characterized by an inflamed tumor microenvironment and HPV oncoproteins are omnipresent, required for cancer survival, and are ideal tumor-specific antigens – we hypothesized that induction and concurrent CTLA-4 and PD-1 immune checkpoint blockade, followed by volume- and dose-adapted IMRT (intensity-modulated radiotherapy), would be an effective alternative to the current standard of care,” said Dr. Gillison, who is a professor of medicine at the University of Texas MD Anderson Cancer Center, Houston.
, according to Robert Ferris, MD, PhD, who moderated the press briefing and was lead author of the nivolumab in metastatic squamous cell carcinoma study. He added that recent trial data suggest this approach should be more effective and create more durable responses.
The new data support the approach. “The trial provides compelling data to support a new approach for treating newly diagnosed HPV-positive head and neck cancers. Our goal is to treat this cancer with immunotherapy alone. The results of this trial make me optimistic that this will be achievable,” Dr. Gillison said.
The study details
The researchers conducted a phase 2 clinical trial, enrolling 35 patients with newly diagnosed HPV-positive oropharynx cancer who were positive for PD-L1 expression.
Patients received 1 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) and 3 mg/kg nivolumab over a 6-week cycle, followed by a second cycle that was accompanied by 40-44 Gy radiotherapy for patients with a complete response in their primary tumor, and a boost to 50-66 based on postinduction treatment volume. The protocol reduced dose to the neck from 52 to 36 Gy. The radiation was delivered to only one nodal echelon beyond the involved node. Standard care delivers radiotherapy to essentially the entire neck, Dr. Gillison said.
Grade 3 or higher adverse events occurred in 66% of patients, the majority of which were attributable to radiotherapy. The complete response rate was 94% at 6 months as assessed by PET scan, and 2-year progression-free survival was 86%. After a median follow-up of 14.9 months, all patients were alive and cancer-free.
Overall response rate was 14% following induction, but 96% showed a histologic treatment effect. Tumor viability was less than 5% in 48% of patients, and a molecular complete response was observed in 30% as measured by plasma cell-free HPV. Patients received 36% less radiation than typical of standard of care, and the dose to critical areas was reduced by 50%.
At the press conference, Dr. Ferris asked Dr. Gillison whether the researchers observed a spike in cell-free HPV DNA before the decline occurred, suggesting evidence of tumor death and DNA release.
“We did see in a remarkable number of patients within 2 weeks of the first dose, a very strong peak in the cell-free HPV DNA, followed by a rapid decline. In those patients who still have viable tumor at the end of induction immunotherapy, we saw a second robust peak in cell-free HPV DNA at the start of radiation, with rapid clearance. So that gave us confidence that (among) those patients who had cell-free HPV clearance by the end of induction, followed by no further detection through radiation, that it’s an excellent surrogate for tumor control,” Dr. Gillison said.
Dr. Gillison has financial relationships with Eisai, Exilixis, Caladrius, iTeos, Istari, Seagen, Sensei, Bicara, Mirati, Coherus, Debiopharm, Kura, Shattuck, Nektar, Ipsen, EMD Serono, Gilead, LXS, BioNTech, Merck, Bristol Myers Squibb, Bayer, Roche, Genocea, NewLink Genetics, Aspyrian, TRM Oncology, Amgen, AstraZeneca, Celgene, and Agenus. Dr. Ferris has financial relationships with Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, and Celgene.
FROM SITC 2022
Latinx and melanoma: Barriers and opportunities
Latinx individuals have a lower overall risk of melanoma than non-Latinx Whites (NLW), but they are more likely to be diagnosed with advanced disease, and experience greater mortality. A new qualitative study of Latinx and low-income NLW individuals in California has revealed some of the socioeconomic and community factors that may play a role in preventing early access to care.
Thicker melanomas, which are more likely to be lethal, are on the rise in the United States among people with lower socioeconomic status (SES), as well as African Americans and Hispanics, and both Black and Latinx people are more likely than NLW people to present with stage 3 or stage 4 disease. “That has really prompted us to look at community engagement and outreach and then really understand the qualitative aspects that are driving individuals into higher risk for melanoma, apart from just limited insurance and access to health care,” said Susan Swetter, MD, who presented the results of the study at the annual meeting of the American Society of Clinical Oncology.
Other studies, such as a Boston-area survey published in 2020, suggest that Hispanics are less likely than Whites to know the meaning of the term melanoma (odds ratio, 0.27; P =.0037), suggesting the need for educational efforts. The authors of that study noted that knowledge of melanoma in 2017, when the survey was conducted, remained essentially unchanged since a previous study was published in 1996.
“Our results support a need for better public educational programs, particularly those geared toward minority populations. Educational programs that are culturally relevant and include specific sections for skin of color have been shown to better promote early melanoma detection in individuals of ethnic minorities and may help decrease the ethnic disparities in melanoma-related mortality. At the patient-physician level, dermatologists may educate their patients, including Hispanic patients, should they choose to perform (skin self-examinations) to specifically inspect the extremities and acral areas, given the higher incidence rates of melanoma on those areas in this population,” the authors wrote.
The goal of the new study is to get a better understanding of the factors that affect attitudes toward health care, and the researchers found a complex mixture that including ethnicity, cultural, gender identity, geography, skin color, gender norms, and socioeconomic status (SES). “Qualitative research can inform our preventive and early detection strategies. For instance, in the Latinx group, there’s a lot of mistrust of health systems, medical providers, and who is providing that knowledge. We have to figure out ways to provide a trusted source of information. Doctors and physicians and health providers tend to be trusted, but there are many barriers to getting lower SES patients into care. We’re now investigating the use of community health workers and even individuals in various settings and community centers, religious settings or religious leaders, where we’ve determined through this focus group research that there is increased trust,” Dr. Swetter said.
The researchers assembled 19 focus groups with 176 total adult participants, interviewing them about perceptions of melanoma risk, prevention and screening strategies and their acceptability, and barriers to melanoma prevention and care. The sample include people from urban and semirural areas; 55%-62% of participants self-identified as Latinx or Hispanic and 26%-27% as NLW.
Latinx and semirural participants reported having minimal conversations with family about melanoma prevention, and those who reported having darker skin perceived their risk from skin cancer as lower. Participants who lived in rural areas, were Latinx, or of low SES status indicated that health care access challenges included out-of-pocket costs, past experiences of physicians showing less concern about them, and little confidence that rural physicians had the needed expertise or would make an appropriate referral.
The study is just the first step in a series of efforts to improve melanoma outcomes in high-risk populations, which is being pursued through Stanford University’s Wipe Out Melanoma–California statewide initiative and research consortium. “What we aim to do is use this knowledge to now design programs to reach the populations who are more likely to present with worse disease, and to prevent that disease from happening. These qualitative analyses are few and far between in the world of melanoma, and we’re really happy to really push this envelope and change the way we deliver preventive and early detection efforts,” said Dr. Swetter, who is a professor of dermatology and director of the pigmented lesion/melanoma and cutaneous oncology programs at Stanford (Calif.) University Medical Center. Dr. Swetter also chairs the National Comprehensive Cancer Network guidelines for cutaneous melanoma.
The study could also improve care of advanced melanoma. “There’s clear evidence that many of these patient and SES factors, economic and knowledge barriers are the same when it comes to getting patients with advanced melanoma into appropriate care and on clinical trials, and that’s true across all races and ethnicities,” said Dr. Swetter.
The ultimate goal of these approaches is to give individuals greater “self-efficacy, such that a person feels more competent to manage his or her own health outcomes. One aspect of this approach is the use of novel technology such as smartphone apps that can track moles or help visualize lesions during teledermatology. “I think that the future of melanoma prevention and early detection is bright, especially if we incorporate novel technologies and engage patients and their communities in the effort. It’s a different strategy, as opposed to the top-down approach of physicians imparting knowledge and providing the exam. Increasing community engagement is critical to reaching the populations at highest risk for advanced disease and getting them into care and detection early,” Dr. Swetter said.
Dr. Swetter has no relevant financial disclosures.
Latinx individuals have a lower overall risk of melanoma than non-Latinx Whites (NLW), but they are more likely to be diagnosed with advanced disease, and experience greater mortality. A new qualitative study of Latinx and low-income NLW individuals in California has revealed some of the socioeconomic and community factors that may play a role in preventing early access to care.
Thicker melanomas, which are more likely to be lethal, are on the rise in the United States among people with lower socioeconomic status (SES), as well as African Americans and Hispanics, and both Black and Latinx people are more likely than NLW people to present with stage 3 or stage 4 disease. “That has really prompted us to look at community engagement and outreach and then really understand the qualitative aspects that are driving individuals into higher risk for melanoma, apart from just limited insurance and access to health care,” said Susan Swetter, MD, who presented the results of the study at the annual meeting of the American Society of Clinical Oncology.
Other studies, such as a Boston-area survey published in 2020, suggest that Hispanics are less likely than Whites to know the meaning of the term melanoma (odds ratio, 0.27; P =.0037), suggesting the need for educational efforts. The authors of that study noted that knowledge of melanoma in 2017, when the survey was conducted, remained essentially unchanged since a previous study was published in 1996.
“Our results support a need for better public educational programs, particularly those geared toward minority populations. Educational programs that are culturally relevant and include specific sections for skin of color have been shown to better promote early melanoma detection in individuals of ethnic minorities and may help decrease the ethnic disparities in melanoma-related mortality. At the patient-physician level, dermatologists may educate their patients, including Hispanic patients, should they choose to perform (skin self-examinations) to specifically inspect the extremities and acral areas, given the higher incidence rates of melanoma on those areas in this population,” the authors wrote.
The goal of the new study is to get a better understanding of the factors that affect attitudes toward health care, and the researchers found a complex mixture that including ethnicity, cultural, gender identity, geography, skin color, gender norms, and socioeconomic status (SES). “Qualitative research can inform our preventive and early detection strategies. For instance, in the Latinx group, there’s a lot of mistrust of health systems, medical providers, and who is providing that knowledge. We have to figure out ways to provide a trusted source of information. Doctors and physicians and health providers tend to be trusted, but there are many barriers to getting lower SES patients into care. We’re now investigating the use of community health workers and even individuals in various settings and community centers, religious settings or religious leaders, where we’ve determined through this focus group research that there is increased trust,” Dr. Swetter said.
The researchers assembled 19 focus groups with 176 total adult participants, interviewing them about perceptions of melanoma risk, prevention and screening strategies and their acceptability, and barriers to melanoma prevention and care. The sample include people from urban and semirural areas; 55%-62% of participants self-identified as Latinx or Hispanic and 26%-27% as NLW.
Latinx and semirural participants reported having minimal conversations with family about melanoma prevention, and those who reported having darker skin perceived their risk from skin cancer as lower. Participants who lived in rural areas, were Latinx, or of low SES status indicated that health care access challenges included out-of-pocket costs, past experiences of physicians showing less concern about them, and little confidence that rural physicians had the needed expertise or would make an appropriate referral.
The study is just the first step in a series of efforts to improve melanoma outcomes in high-risk populations, which is being pursued through Stanford University’s Wipe Out Melanoma–California statewide initiative and research consortium. “What we aim to do is use this knowledge to now design programs to reach the populations who are more likely to present with worse disease, and to prevent that disease from happening. These qualitative analyses are few and far between in the world of melanoma, and we’re really happy to really push this envelope and change the way we deliver preventive and early detection efforts,” said Dr. Swetter, who is a professor of dermatology and director of the pigmented lesion/melanoma and cutaneous oncology programs at Stanford (Calif.) University Medical Center. Dr. Swetter also chairs the National Comprehensive Cancer Network guidelines for cutaneous melanoma.
The study could also improve care of advanced melanoma. “There’s clear evidence that many of these patient and SES factors, economic and knowledge barriers are the same when it comes to getting patients with advanced melanoma into appropriate care and on clinical trials, and that’s true across all races and ethnicities,” said Dr. Swetter.
The ultimate goal of these approaches is to give individuals greater “self-efficacy, such that a person feels more competent to manage his or her own health outcomes. One aspect of this approach is the use of novel technology such as smartphone apps that can track moles or help visualize lesions during teledermatology. “I think that the future of melanoma prevention and early detection is bright, especially if we incorporate novel technologies and engage patients and their communities in the effort. It’s a different strategy, as opposed to the top-down approach of physicians imparting knowledge and providing the exam. Increasing community engagement is critical to reaching the populations at highest risk for advanced disease and getting them into care and detection early,” Dr. Swetter said.
Dr. Swetter has no relevant financial disclosures.
Latinx individuals have a lower overall risk of melanoma than non-Latinx Whites (NLW), but they are more likely to be diagnosed with advanced disease, and experience greater mortality. A new qualitative study of Latinx and low-income NLW individuals in California has revealed some of the socioeconomic and community factors that may play a role in preventing early access to care.
Thicker melanomas, which are more likely to be lethal, are on the rise in the United States among people with lower socioeconomic status (SES), as well as African Americans and Hispanics, and both Black and Latinx people are more likely than NLW people to present with stage 3 or stage 4 disease. “That has really prompted us to look at community engagement and outreach and then really understand the qualitative aspects that are driving individuals into higher risk for melanoma, apart from just limited insurance and access to health care,” said Susan Swetter, MD, who presented the results of the study at the annual meeting of the American Society of Clinical Oncology.
Other studies, such as a Boston-area survey published in 2020, suggest that Hispanics are less likely than Whites to know the meaning of the term melanoma (odds ratio, 0.27; P =.0037), suggesting the need for educational efforts. The authors of that study noted that knowledge of melanoma in 2017, when the survey was conducted, remained essentially unchanged since a previous study was published in 1996.
“Our results support a need for better public educational programs, particularly those geared toward minority populations. Educational programs that are culturally relevant and include specific sections for skin of color have been shown to better promote early melanoma detection in individuals of ethnic minorities and may help decrease the ethnic disparities in melanoma-related mortality. At the patient-physician level, dermatologists may educate their patients, including Hispanic patients, should they choose to perform (skin self-examinations) to specifically inspect the extremities and acral areas, given the higher incidence rates of melanoma on those areas in this population,” the authors wrote.
The goal of the new study is to get a better understanding of the factors that affect attitudes toward health care, and the researchers found a complex mixture that including ethnicity, cultural, gender identity, geography, skin color, gender norms, and socioeconomic status (SES). “Qualitative research can inform our preventive and early detection strategies. For instance, in the Latinx group, there’s a lot of mistrust of health systems, medical providers, and who is providing that knowledge. We have to figure out ways to provide a trusted source of information. Doctors and physicians and health providers tend to be trusted, but there are many barriers to getting lower SES patients into care. We’re now investigating the use of community health workers and even individuals in various settings and community centers, religious settings or religious leaders, where we’ve determined through this focus group research that there is increased trust,” Dr. Swetter said.
The researchers assembled 19 focus groups with 176 total adult participants, interviewing them about perceptions of melanoma risk, prevention and screening strategies and their acceptability, and barriers to melanoma prevention and care. The sample include people from urban and semirural areas; 55%-62% of participants self-identified as Latinx or Hispanic and 26%-27% as NLW.
Latinx and semirural participants reported having minimal conversations with family about melanoma prevention, and those who reported having darker skin perceived their risk from skin cancer as lower. Participants who lived in rural areas, were Latinx, or of low SES status indicated that health care access challenges included out-of-pocket costs, past experiences of physicians showing less concern about them, and little confidence that rural physicians had the needed expertise or would make an appropriate referral.
The study is just the first step in a series of efforts to improve melanoma outcomes in high-risk populations, which is being pursued through Stanford University’s Wipe Out Melanoma–California statewide initiative and research consortium. “What we aim to do is use this knowledge to now design programs to reach the populations who are more likely to present with worse disease, and to prevent that disease from happening. These qualitative analyses are few and far between in the world of melanoma, and we’re really happy to really push this envelope and change the way we deliver preventive and early detection efforts,” said Dr. Swetter, who is a professor of dermatology and director of the pigmented lesion/melanoma and cutaneous oncology programs at Stanford (Calif.) University Medical Center. Dr. Swetter also chairs the National Comprehensive Cancer Network guidelines for cutaneous melanoma.
The study could also improve care of advanced melanoma. “There’s clear evidence that many of these patient and SES factors, economic and knowledge barriers are the same when it comes to getting patients with advanced melanoma into appropriate care and on clinical trials, and that’s true across all races and ethnicities,” said Dr. Swetter.
The ultimate goal of these approaches is to give individuals greater “self-efficacy, such that a person feels more competent to manage his or her own health outcomes. One aspect of this approach is the use of novel technology such as smartphone apps that can track moles or help visualize lesions during teledermatology. “I think that the future of melanoma prevention and early detection is bright, especially if we incorporate novel technologies and engage patients and their communities in the effort. It’s a different strategy, as opposed to the top-down approach of physicians imparting knowledge and providing the exam. Increasing community engagement is critical to reaching the populations at highest risk for advanced disease and getting them into care and detection early,” Dr. Swetter said.
Dr. Swetter has no relevant financial disclosures.
FROM ASCO 2022
Study affirms shorter regimens for drug-resistant tuberculosis
Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.
The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.
The study was published in The Lancet.
The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.
The study’s first stage, STREAM stage 1, showed that The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
Seeking shorter treatment for better outcomes
STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).
The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.
The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.
For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).
Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).
For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.
In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.
Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.
Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.
The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.
“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.
“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.
Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).
“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
‘A revolution in MDR tuberculosis’
“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.
Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.
The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.
However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”
The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.
A version of this article first appeared on Medscape.com.
Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.
The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.
The study was published in The Lancet.
The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.
The study’s first stage, STREAM stage 1, showed that The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
Seeking shorter treatment for better outcomes
STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).
The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.
The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.
For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).
Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).
For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.
In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.
Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.
Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.
The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.
“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.
“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.
Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).
“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
‘A revolution in MDR tuberculosis’
“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.
Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.
The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.
However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”
The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.
A version of this article first appeared on Medscape.com.
Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.
The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.
The study was published in The Lancet.
The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.
The study’s first stage, STREAM stage 1, showed that The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
Seeking shorter treatment for better outcomes
STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).
The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.
The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.
For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).
Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).
For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.
In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.
Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.
Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.
The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.
“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.
“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.
Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).
“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
‘A revolution in MDR tuberculosis’
“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.
Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.
The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.
However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”
The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.
A version of this article first appeared on Medscape.com.
Cardiovascular societies less apt to recognize women, minorities
Major cardiovascular societies are more apt to give out awards to men and White individuals than to women and minorities, according to a look at 2 decades’ worth of data.
“Women received significantly fewer awards than men in all societies, countries, and award categories,” author Martha Gulati, MD, director of preventive cardiology at Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a news release. “This bias may be responsible for preventing underrepresented groups from ascending the academic ladder and receiving senior awards like lifetime achievement awards.”
The study was published online in the Journal of the American College of Cardiology.
A slow climb
The findings are based on a review of honors given from 2000 to 2021 by the ACC, the American Heart Association, the American Society of Echocardiography, the Society for Cardiovascular Angiography and Interventions, the Heart Rhythm Society, the European Society of Cardiology, and the Canadian Cardiovascular Society.
Among the 173 unique awards, 94 were given by the AHA, 27 by the HRS, 17 by the ACC, 16 by the CCS, 8 by the ASE, 7 by the ESC, and 4 by the SCAI. There were 3,044 recipients of these awards, including 2,830 unique awardees.
The vast majority of the awardees were White (75.2%), with Asian, Hispanic/Latino, and Black awardees representing just 18.9%, 4.5%, and 1.4% of the total awardees, respectively.
In a gender analysis, the researchers looked at 169 awards after excluding female-specific awards. These 169 awards were distributed to 2,995 recipients. More than three-quarters of these awardees (76.2%) were men, with women making up less than one-quarter (23.8%).
Encouragingly, there was an increasing trend in recognition of women over time, with 7.7% of female awardees in 2000 and climbing to 31.2% in 2021 (average annual percentage change, 6.6%; P < .05).
The distribution of awards also became more racially/ethnically diverse over time; in 2000, 92.3% of awardees were White versus 62.8% in 2021 (AAPC, –1.4%; P < .001).
There was also a significant increase in Asian (AAPC, 5.7%; P < .001), Hispanic/Latino (AAPC, 4.8%; P = .040), and Black (AAPC, 7.8%; P < .05) honorees.
Core influencers
By award type, women received fewer leadership awards than men, “which can be attributed to fewer leadership opportunities for women and a lack of acknowledgment of leadership responsibilities fulfilled by women,” the researchers said.
Award recipients with a PhD degree were nearly gender balanced (48.2% women), whereas men formed an overwhelming majority of awardees with an MD (84.7%).
Awards with male eponyms had fewer women recipients than did noneponymous awards (20.9% vs. 23.2%; P < .01).
“Male-eponymous awards can deter women applicants and give a subtle hint to selection committees to favor men as winners, creating an implicit bias,” the researchers said.
“Given the increased emphasis on redesigning cardiovascular health care delivery by incorporating the tenets of diversity, equity, and inclusion (DEI), cardiovascular societies have a significant role as core influencers,” Dr. Gulati and colleagues wrote.
They said that equitable award distribution can be a “key strategy to celebrate women and diverse members of the cardiovascular workforce and promulgate DEI.”
“Recognition of their contributions is pivotal to enhancing their self-perception. In addition to boosting confidence, receiving an award can also catalyze their career trajectory,” the authors added.
The study had no specific funding. The authors have declared no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Major cardiovascular societies are more apt to give out awards to men and White individuals than to women and minorities, according to a look at 2 decades’ worth of data.
“Women received significantly fewer awards than men in all societies, countries, and award categories,” author Martha Gulati, MD, director of preventive cardiology at Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a news release. “This bias may be responsible for preventing underrepresented groups from ascending the academic ladder and receiving senior awards like lifetime achievement awards.”
The study was published online in the Journal of the American College of Cardiology.
A slow climb
The findings are based on a review of honors given from 2000 to 2021 by the ACC, the American Heart Association, the American Society of Echocardiography, the Society for Cardiovascular Angiography and Interventions, the Heart Rhythm Society, the European Society of Cardiology, and the Canadian Cardiovascular Society.
Among the 173 unique awards, 94 were given by the AHA, 27 by the HRS, 17 by the ACC, 16 by the CCS, 8 by the ASE, 7 by the ESC, and 4 by the SCAI. There were 3,044 recipients of these awards, including 2,830 unique awardees.
The vast majority of the awardees were White (75.2%), with Asian, Hispanic/Latino, and Black awardees representing just 18.9%, 4.5%, and 1.4% of the total awardees, respectively.
In a gender analysis, the researchers looked at 169 awards after excluding female-specific awards. These 169 awards were distributed to 2,995 recipients. More than three-quarters of these awardees (76.2%) were men, with women making up less than one-quarter (23.8%).
Encouragingly, there was an increasing trend in recognition of women over time, with 7.7% of female awardees in 2000 and climbing to 31.2% in 2021 (average annual percentage change, 6.6%; P < .05).
The distribution of awards also became more racially/ethnically diverse over time; in 2000, 92.3% of awardees were White versus 62.8% in 2021 (AAPC, –1.4%; P < .001).
There was also a significant increase in Asian (AAPC, 5.7%; P < .001), Hispanic/Latino (AAPC, 4.8%; P = .040), and Black (AAPC, 7.8%; P < .05) honorees.
Core influencers
By award type, women received fewer leadership awards than men, “which can be attributed to fewer leadership opportunities for women and a lack of acknowledgment of leadership responsibilities fulfilled by women,” the researchers said.
Award recipients with a PhD degree were nearly gender balanced (48.2% women), whereas men formed an overwhelming majority of awardees with an MD (84.7%).
Awards with male eponyms had fewer women recipients than did noneponymous awards (20.9% vs. 23.2%; P < .01).
“Male-eponymous awards can deter women applicants and give a subtle hint to selection committees to favor men as winners, creating an implicit bias,” the researchers said.
“Given the increased emphasis on redesigning cardiovascular health care delivery by incorporating the tenets of diversity, equity, and inclusion (DEI), cardiovascular societies have a significant role as core influencers,” Dr. Gulati and colleagues wrote.
They said that equitable award distribution can be a “key strategy to celebrate women and diverse members of the cardiovascular workforce and promulgate DEI.”
“Recognition of their contributions is pivotal to enhancing their self-perception. In addition to boosting confidence, receiving an award can also catalyze their career trajectory,” the authors added.
The study had no specific funding. The authors have declared no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Major cardiovascular societies are more apt to give out awards to men and White individuals than to women and minorities, according to a look at 2 decades’ worth of data.
“Women received significantly fewer awards than men in all societies, countries, and award categories,” author Martha Gulati, MD, director of preventive cardiology at Smidt Heart Institute at Cedars-Sinai, Los Angeles, said in a news release. “This bias may be responsible for preventing underrepresented groups from ascending the academic ladder and receiving senior awards like lifetime achievement awards.”
The study was published online in the Journal of the American College of Cardiology.
A slow climb
The findings are based on a review of honors given from 2000 to 2021 by the ACC, the American Heart Association, the American Society of Echocardiography, the Society for Cardiovascular Angiography and Interventions, the Heart Rhythm Society, the European Society of Cardiology, and the Canadian Cardiovascular Society.
Among the 173 unique awards, 94 were given by the AHA, 27 by the HRS, 17 by the ACC, 16 by the CCS, 8 by the ASE, 7 by the ESC, and 4 by the SCAI. There were 3,044 recipients of these awards, including 2,830 unique awardees.
The vast majority of the awardees were White (75.2%), with Asian, Hispanic/Latino, and Black awardees representing just 18.9%, 4.5%, and 1.4% of the total awardees, respectively.
In a gender analysis, the researchers looked at 169 awards after excluding female-specific awards. These 169 awards were distributed to 2,995 recipients. More than three-quarters of these awardees (76.2%) were men, with women making up less than one-quarter (23.8%).
Encouragingly, there was an increasing trend in recognition of women over time, with 7.7% of female awardees in 2000 and climbing to 31.2% in 2021 (average annual percentage change, 6.6%; P < .05).
The distribution of awards also became more racially/ethnically diverse over time; in 2000, 92.3% of awardees were White versus 62.8% in 2021 (AAPC, –1.4%; P < .001).
There was also a significant increase in Asian (AAPC, 5.7%; P < .001), Hispanic/Latino (AAPC, 4.8%; P = .040), and Black (AAPC, 7.8%; P < .05) honorees.
Core influencers
By award type, women received fewer leadership awards than men, “which can be attributed to fewer leadership opportunities for women and a lack of acknowledgment of leadership responsibilities fulfilled by women,” the researchers said.
Award recipients with a PhD degree were nearly gender balanced (48.2% women), whereas men formed an overwhelming majority of awardees with an MD (84.7%).
Awards with male eponyms had fewer women recipients than did noneponymous awards (20.9% vs. 23.2%; P < .01).
“Male-eponymous awards can deter women applicants and give a subtle hint to selection committees to favor men as winners, creating an implicit bias,” the researchers said.
“Given the increased emphasis on redesigning cardiovascular health care delivery by incorporating the tenets of diversity, equity, and inclusion (DEI), cardiovascular societies have a significant role as core influencers,” Dr. Gulati and colleagues wrote.
They said that equitable award distribution can be a “key strategy to celebrate women and diverse members of the cardiovascular workforce and promulgate DEI.”
“Recognition of their contributions is pivotal to enhancing their self-perception. In addition to boosting confidence, receiving an award can also catalyze their career trajectory,” the authors added.
The study had no specific funding. The authors have declared no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
New genetic variant linked to maturity-onset diabetes of the young
A newly discovered genetic variant that is associated with type 2 diabetes (T2D) is responsible for almost 7% of all diabetes cases in Greenland, according to a whole-genome sequencing analysis of 448 Greenlandic Inuit individuals.
The variant, identified as c.1108G>T, “has the largest population impact of any previously reported variant” within the HNF1A gene – a gene that can cause maturity-onset diabetes of the young (MODY), reported senior author Torben Hansen, MD, PhD, of the University of Copenhagen, and colleagues in The Lancet Regional Health–Europe. The c.1108G>T variant does not cause MODY, but other variants within the HNF1A gene do. However, carriers of this variant, which is present in 1.9% of the Greenlandic Inuit population and has not been found elsewhere, have normal insulin sensitivity, but decreased beta-cell function and a more than fourfold risk of developing type 2 diabetes. “This adds to a previous discovery that about 11% of all diabetes in Greenlandic Inuit is explained by a mutation in the TBC1D4 variant,” Dr. Hansen told this publication. “Thus 1 in 5 patients diagnosed with type 2 diabetes in Greenland have a specific mutation explaining their diabetes. In European populations only about 1%-2% of patients diagnosed with type 2 diabetes have a known genetic etiology.”
The finding “provides new avenues to subgroup patients, detect diabetes in family members, and pursue precision treatment trials,” noted the authors, although they acknowledged that treatment choices for individuals with this variant still need to be explored. “We know from HNF1A-mutation carriers with European ancestry that they benefit from sulfonylurea treatment,” said Dr. Hansen. “However, we have not yet done treatment studies in Inuit.” The investigators noted that “it is not always the case that variants in HNF1A result in an increased insulin secretory response to sulfonylurea. ... Whether carriers of the c.1108G>T variant could benefit from treatment with sulfonylurea should be pursued within the context of a randomized clinical trial establishing both short- and long-term efficacy of sulfonylurea in these patients.”
A total of 4,497 study participants were randomly sampled from two cross-sectional cohorts in an adult Greenlandic population health survey. Among 448 participants who had whole genome sequencing, 14 known MODY genes were screened for both previously identified as well as novel variants. This identified the c.1108G>T variant, which was then genotyped in the full cohort in order to estimate an allele frequency of 1.3% in the general Greenlandic population, and 1.9% in the Inuit component. The variant was not found in genome sequences of other populations.
The researchers then tested the association of the variant with T2D and showed strong association with T2D (odds ratio, 4.35) and higher hemoglobin A1c levels.
“This is very well-conducted and exciting research that highlights the importance of studying the genetics of diverse populations,” said Miriam Udler, MD, PhD, director of the Massachusetts General Diabetes Genetics Clinic, and assistant professor at Harvard University, both in Boston. “This manuscript builds on prior work from the researchers identifying another genetic variant specific to the Greenlandic Inuit population in the gene TBC1D4,” she added. “About 3.8% of people in this population carry two copies of the TBC1D4 variant and have about a 10-fold increased risk of diabetes. Together the two variants affect 18% of Greenlanders with diabetes.”
With its fourfold increased risk of diabetes, the new variant falls into “an ever-growing category” of “intermediate risk” genetic variants, explained Dr. Udler – “meaning that they have a large impact on diabetes risk, but cannot fully predict whether someone will get diabetes. The contribution of additional risk factors is particularly important for ‘intermediate risk’ genetic variants,” she added. “Thus, clinically, we can tell patients who have variants such as HNF1A c.1108>T that they are at substantial increased risk of diabetes, but that many will not develop diabetes. And for those who do develop diabetes, we are not yet able to advise on particular therapeutic strategies.”
Still, she emphasized, the importance of studying diverse populations with specific genetic risk factors is the end-goal of precision medicine. “An active area of research is determining whether and how to return such information about ‘intermediate risk’ variants to patients who get clinical genetic testing for diabetes, since typically only variants that are very high risk ... are returned in clinical testing reports.” Dr. Udler added that “many more such “intermediate risk’ variants likely exist in all populations, but have yet to be characterized because they are less common than HNF1A c.1108>T; however, ongoing worldwide efforts to increase the sample sizes of human genetic studies will facilitate such discovery.”
The study was funded by Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen’s Foundation. Dr. Hansen and Dr. Udler had no disclosures.
A newly discovered genetic variant that is associated with type 2 diabetes (T2D) is responsible for almost 7% of all diabetes cases in Greenland, according to a whole-genome sequencing analysis of 448 Greenlandic Inuit individuals.
The variant, identified as c.1108G>T, “has the largest population impact of any previously reported variant” within the HNF1A gene – a gene that can cause maturity-onset diabetes of the young (MODY), reported senior author Torben Hansen, MD, PhD, of the University of Copenhagen, and colleagues in The Lancet Regional Health–Europe. The c.1108G>T variant does not cause MODY, but other variants within the HNF1A gene do. However, carriers of this variant, which is present in 1.9% of the Greenlandic Inuit population and has not been found elsewhere, have normal insulin sensitivity, but decreased beta-cell function and a more than fourfold risk of developing type 2 diabetes. “This adds to a previous discovery that about 11% of all diabetes in Greenlandic Inuit is explained by a mutation in the TBC1D4 variant,” Dr. Hansen told this publication. “Thus 1 in 5 patients diagnosed with type 2 diabetes in Greenland have a specific mutation explaining their diabetes. In European populations only about 1%-2% of patients diagnosed with type 2 diabetes have a known genetic etiology.”
The finding “provides new avenues to subgroup patients, detect diabetes in family members, and pursue precision treatment trials,” noted the authors, although they acknowledged that treatment choices for individuals with this variant still need to be explored. “We know from HNF1A-mutation carriers with European ancestry that they benefit from sulfonylurea treatment,” said Dr. Hansen. “However, we have not yet done treatment studies in Inuit.” The investigators noted that “it is not always the case that variants in HNF1A result in an increased insulin secretory response to sulfonylurea. ... Whether carriers of the c.1108G>T variant could benefit from treatment with sulfonylurea should be pursued within the context of a randomized clinical trial establishing both short- and long-term efficacy of sulfonylurea in these patients.”
A total of 4,497 study participants were randomly sampled from two cross-sectional cohorts in an adult Greenlandic population health survey. Among 448 participants who had whole genome sequencing, 14 known MODY genes were screened for both previously identified as well as novel variants. This identified the c.1108G>T variant, which was then genotyped in the full cohort in order to estimate an allele frequency of 1.3% in the general Greenlandic population, and 1.9% in the Inuit component. The variant was not found in genome sequences of other populations.
The researchers then tested the association of the variant with T2D and showed strong association with T2D (odds ratio, 4.35) and higher hemoglobin A1c levels.
“This is very well-conducted and exciting research that highlights the importance of studying the genetics of diverse populations,” said Miriam Udler, MD, PhD, director of the Massachusetts General Diabetes Genetics Clinic, and assistant professor at Harvard University, both in Boston. “This manuscript builds on prior work from the researchers identifying another genetic variant specific to the Greenlandic Inuit population in the gene TBC1D4,” she added. “About 3.8% of people in this population carry two copies of the TBC1D4 variant and have about a 10-fold increased risk of diabetes. Together the two variants affect 18% of Greenlanders with diabetes.”
With its fourfold increased risk of diabetes, the new variant falls into “an ever-growing category” of “intermediate risk” genetic variants, explained Dr. Udler – “meaning that they have a large impact on diabetes risk, but cannot fully predict whether someone will get diabetes. The contribution of additional risk factors is particularly important for ‘intermediate risk’ genetic variants,” she added. “Thus, clinically, we can tell patients who have variants such as HNF1A c.1108>T that they are at substantial increased risk of diabetes, but that many will not develop diabetes. And for those who do develop diabetes, we are not yet able to advise on particular therapeutic strategies.”
Still, she emphasized, the importance of studying diverse populations with specific genetic risk factors is the end-goal of precision medicine. “An active area of research is determining whether and how to return such information about ‘intermediate risk’ variants to patients who get clinical genetic testing for diabetes, since typically only variants that are very high risk ... are returned in clinical testing reports.” Dr. Udler added that “many more such “intermediate risk’ variants likely exist in all populations, but have yet to be characterized because they are less common than HNF1A c.1108>T; however, ongoing worldwide efforts to increase the sample sizes of human genetic studies will facilitate such discovery.”
The study was funded by Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen’s Foundation. Dr. Hansen and Dr. Udler had no disclosures.
A newly discovered genetic variant that is associated with type 2 diabetes (T2D) is responsible for almost 7% of all diabetes cases in Greenland, according to a whole-genome sequencing analysis of 448 Greenlandic Inuit individuals.
The variant, identified as c.1108G>T, “has the largest population impact of any previously reported variant” within the HNF1A gene – a gene that can cause maturity-onset diabetes of the young (MODY), reported senior author Torben Hansen, MD, PhD, of the University of Copenhagen, and colleagues in The Lancet Regional Health–Europe. The c.1108G>T variant does not cause MODY, but other variants within the HNF1A gene do. However, carriers of this variant, which is present in 1.9% of the Greenlandic Inuit population and has not been found elsewhere, have normal insulin sensitivity, but decreased beta-cell function and a more than fourfold risk of developing type 2 diabetes. “This adds to a previous discovery that about 11% of all diabetes in Greenlandic Inuit is explained by a mutation in the TBC1D4 variant,” Dr. Hansen told this publication. “Thus 1 in 5 patients diagnosed with type 2 diabetes in Greenland have a specific mutation explaining their diabetes. In European populations only about 1%-2% of patients diagnosed with type 2 diabetes have a known genetic etiology.”
The finding “provides new avenues to subgroup patients, detect diabetes in family members, and pursue precision treatment trials,” noted the authors, although they acknowledged that treatment choices for individuals with this variant still need to be explored. “We know from HNF1A-mutation carriers with European ancestry that they benefit from sulfonylurea treatment,” said Dr. Hansen. “However, we have not yet done treatment studies in Inuit.” The investigators noted that “it is not always the case that variants in HNF1A result in an increased insulin secretory response to sulfonylurea. ... Whether carriers of the c.1108G>T variant could benefit from treatment with sulfonylurea should be pursued within the context of a randomized clinical trial establishing both short- and long-term efficacy of sulfonylurea in these patients.”
A total of 4,497 study participants were randomly sampled from two cross-sectional cohorts in an adult Greenlandic population health survey. Among 448 participants who had whole genome sequencing, 14 known MODY genes were screened for both previously identified as well as novel variants. This identified the c.1108G>T variant, which was then genotyped in the full cohort in order to estimate an allele frequency of 1.3% in the general Greenlandic population, and 1.9% in the Inuit component. The variant was not found in genome sequences of other populations.
The researchers then tested the association of the variant with T2D and showed strong association with T2D (odds ratio, 4.35) and higher hemoglobin A1c levels.
“This is very well-conducted and exciting research that highlights the importance of studying the genetics of diverse populations,” said Miriam Udler, MD, PhD, director of the Massachusetts General Diabetes Genetics Clinic, and assistant professor at Harvard University, both in Boston. “This manuscript builds on prior work from the researchers identifying another genetic variant specific to the Greenlandic Inuit population in the gene TBC1D4,” she added. “About 3.8% of people in this population carry two copies of the TBC1D4 variant and have about a 10-fold increased risk of diabetes. Together the two variants affect 18% of Greenlanders with diabetes.”
With its fourfold increased risk of diabetes, the new variant falls into “an ever-growing category” of “intermediate risk” genetic variants, explained Dr. Udler – “meaning that they have a large impact on diabetes risk, but cannot fully predict whether someone will get diabetes. The contribution of additional risk factors is particularly important for ‘intermediate risk’ genetic variants,” she added. “Thus, clinically, we can tell patients who have variants such as HNF1A c.1108>T that they are at substantial increased risk of diabetes, but that many will not develop diabetes. And for those who do develop diabetes, we are not yet able to advise on particular therapeutic strategies.”
Still, she emphasized, the importance of studying diverse populations with specific genetic risk factors is the end-goal of precision medicine. “An active area of research is determining whether and how to return such information about ‘intermediate risk’ variants to patients who get clinical genetic testing for diabetes, since typically only variants that are very high risk ... are returned in clinical testing reports.” Dr. Udler added that “many more such “intermediate risk’ variants likely exist in all populations, but have yet to be characterized because they are less common than HNF1A c.1108>T; however, ongoing worldwide efforts to increase the sample sizes of human genetic studies will facilitate such discovery.”
The study was funded by Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen’s Foundation. Dr. Hansen and Dr. Udler had no disclosures.
FROM THE LANCET REGIONAL HEALTH–EUROPE
Future HIV PrEP innovations aim to address adherence, women’s health, and combination treatments
TAMPA – Pre-exposure prophylaxis (PrEP) has shown to be effective in many clinical and real-world studies, but concerns remain, according to research presented at the annual meeting of the Association of Nurses in AIDS Care (ANAC).
Only about 20% of people who could benefit from PrEP use the preventative medication, for example. Another concern is adherence, as regular use generally drops off over time, rarely lasting more than a few months for most people.
Furthermore, most studies to date evaluated safety and effectiveness of PrEP options among men who have sex with men. Now the focus is increasing on other populations, including women at risk of HIV exposure.
Researchers working on new forms and formulations of PrEP are looking for ways to address those challenges.
said Craig W. Hendrix, MD, professor and director of the Division of Clinical Pharmacology at Johns Hopkins University School of Medicine, Baltimore.
“What I hear a lot of folks say [is] there are two or three options for PrEP, so why do we need more? We need choices that fit into a broader range of lifestyles,” Dr. Hendrix said.
For example, a medically fortified douche containing PrEP might be more likely to be used by people who use a douche before or after sex on a regular basis. This is called a “behaviorally congruent” strategy, Dr. Hendrix said.
In addition to a medical douche, formulations designed to continuously deliver PrEP, such as a subdermal implant, are in the works as well.
Another option for women, the dapivirine vaginal ring, is available internationally but not in the United States. “It was withdrawn from [Food and Drug Administration] consideration by the sponsor. I think it’s a huge loss not to have that,” Dr. Hendrix said.
During development, “frequent expulsions forced reformulation to a less stiff ring,” Dr. Hendrix said. “I don’t imagine that’s terrific, but it shows how important it is to have something that fits the anatomy and the lifestyle.”
“Currently, we have in the U.S. three licensed, really terrific options for PrEP, and they’re all for men that have sex with men and transgender women,” Dr. Hendrix said.
Three current options
The three current PrEP regimens in the United States often go by their abbreviations: F/TDF, F/TAF, and CAB-IM.
- F/TDF is emtricitabine (F) 200 mg in combination with tenofovir disoproxil fumarate (TDF) 300 mg (Truvada, Gilead or generics)
- F/TAF is emtricitabine (F) 200 mg in combination with tenofovir alafenamide (TAF) 25 mg (Descovy, Gilead)
- CAB-IM is cabotegravir (CAB) 600 mg injection (Apretude, GlaxoSmithKline)
There is an important distinction: Daily oral PrEP with F/TDF is recommended to prevent HIV infection among all people at risk through sex or injection drug use. Daily oral PrEP with F/TAF is recommended to prevent HIV infection among people at risk through sex, excluding people at risk through receptive vaginal sex, the CDC notes.
The cost-effectiveness of the injection remains a potential issue, Dr. Hendrix said. On the other hand, “cost-effectiveness goes out the window if there is no adherence.”
An active pipeline
There are 24 new PrEP products in development, as well as 24 other multipurpose prevention technologies (MPTs), which are combination products containing PrEP and one or two other medications.
These 48 products include 28 unique antiviral and contraceptive drugs and 12 delivery methods or formulations. “Why so many?” Dr. Hendrix asked. “Many will not make it through development.”
Pills that include HIV PrEP and contraception or PrEP and sexually transmitted infection (STI) treatment are being evaluated, for example. “HIV risk, pregnancy risk, and other viral STIs overlap. Ideally, you can have one target for all three. That would increase efficiency of dosing and adherence,” Dr. Hendrix said.
Dual prevention pills (DPPs) hypothetically provide HIV PrEP and contraception better than either product alone, Dr. Hendrix said. Plans are to market them as family planning or women’s health products to avoid any stigma or distrust associated with HIV PrEP. An initial rollout is planned in 2024 in sub-Saharan Africa where the unmet need is highest, he added.
“Imagine how effective this could be in women in the United States,” Dr. Hendrix said. “My hope is fourth-quarter 2024” availability in the United States.
A way to prevent STIs and HIV in an all-in-one product “would be terrific,” Dr. Hendrix said.
“I think we’re going to see a lot more innovation going in that direction. The pill is close. The other things are going to be further off because the regulatory pathway is a little more complicated.”
Longer lasting protection?
All of the innovations have gone one of two directions, Dr. Hendrix said. One direction is to make PrEP even longer acting, “so that you have even less to worry [about] in terms of adherence.”
Going forward, “most of the focus has all been on continuously acting or long-active PrEP. It’s getting longer and longer: We’ve got 2 months, and they’re looking at a 6-month subcutaneous injection,” Dr. Hendrix said. The investigational agent lenacapavir is in development as PrEP, as well as for HIV treatment.
“This could get us from 2 to 6 months,” Dr. Hendrix said.
Some of the subcutaneous implants look as if they could provide PrEP for up to 12 months, he added. “An implant could also avoid peaks and troughs with bi-monthly injections.”
On-demand PrEP
The other direction is on-demand. “This is for the folks that don’t want drug in their body all the time. They only want it when they need it. And a twist on that ... is actually using products that are already used with sex now but medicating them.”
On-demand rectal options include a medicated douche and a fast-dissolving insert or suppository.
Fast-dissolving vaginal inserts are also in development. “These inserts are small, easy to store, inexpensive, and possibly inapparent to a partner,” Dr. Hendrix said.
Phase 2 studies will need to determine if these products “fit into folks’ active sex lives,” he said. “There’s still a need for human-friendly, human-designed products.”
A rectal microbicide that got as far as Phase 2 research provides a cautionary tale. The concentrations and the biology worked fine, Dr. Hendrix said. “It was a gel with an applicator, and it just was not liked by the folks in the study.” He added, “Your adherence is going to be in the tank if you’ve got a product that people don’t like to use.”
‘Extremely excited’
Asked for her perspective on Dr. Hendrix’s presentation, session moderator Rasheeta D. Chandler, PhD, RN, an associate professor at the Nell Hodgson Woodruff School of Nursing at Emory University, Atlanta, said: “I am extremely excited, because I work with cisgender women, particularly with underserved women and women of color, and there’s a tendency to focus on men who have sex with men.”
“I understand, because they are the population that is most affected, but Black women are also extremely affected by this disease,” Dr. Chandler told this news organization.
Dr. Chandler applauded Dr. Hendrix for addressing women’s health needs as well and not treating PrEP in women “as an afterthought.”
“Finally, our voices are being heard that [PrEP] should be equitable across all different types of individuals who identify differently in a sexual context,” Dr. Chandler said.
More work is warranted to evaluate PrEP in other populations, including transgender men and individuals who inject drugs, Dr. Hendrix said.
For more information and updates on HIV PrEP and MPTs, visit the website of the nonprofit AIDS Vaccine Advocacy Coalition.
Dr. Hendrix has disclosed receiving research grants from Gilead and Merck. Dr. Chandler has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TAMPA – Pre-exposure prophylaxis (PrEP) has shown to be effective in many clinical and real-world studies, but concerns remain, according to research presented at the annual meeting of the Association of Nurses in AIDS Care (ANAC).
Only about 20% of people who could benefit from PrEP use the preventative medication, for example. Another concern is adherence, as regular use generally drops off over time, rarely lasting more than a few months for most people.
Furthermore, most studies to date evaluated safety and effectiveness of PrEP options among men who have sex with men. Now the focus is increasing on other populations, including women at risk of HIV exposure.
Researchers working on new forms and formulations of PrEP are looking for ways to address those challenges.
said Craig W. Hendrix, MD, professor and director of the Division of Clinical Pharmacology at Johns Hopkins University School of Medicine, Baltimore.
“What I hear a lot of folks say [is] there are two or three options for PrEP, so why do we need more? We need choices that fit into a broader range of lifestyles,” Dr. Hendrix said.
For example, a medically fortified douche containing PrEP might be more likely to be used by people who use a douche before or after sex on a regular basis. This is called a “behaviorally congruent” strategy, Dr. Hendrix said.
In addition to a medical douche, formulations designed to continuously deliver PrEP, such as a subdermal implant, are in the works as well.
Another option for women, the dapivirine vaginal ring, is available internationally but not in the United States. “It was withdrawn from [Food and Drug Administration] consideration by the sponsor. I think it’s a huge loss not to have that,” Dr. Hendrix said.
During development, “frequent expulsions forced reformulation to a less stiff ring,” Dr. Hendrix said. “I don’t imagine that’s terrific, but it shows how important it is to have something that fits the anatomy and the lifestyle.”
“Currently, we have in the U.S. three licensed, really terrific options for PrEP, and they’re all for men that have sex with men and transgender women,” Dr. Hendrix said.
Three current options
The three current PrEP regimens in the United States often go by their abbreviations: F/TDF, F/TAF, and CAB-IM.
- F/TDF is emtricitabine (F) 200 mg in combination with tenofovir disoproxil fumarate (TDF) 300 mg (Truvada, Gilead or generics)
- F/TAF is emtricitabine (F) 200 mg in combination with tenofovir alafenamide (TAF) 25 mg (Descovy, Gilead)
- CAB-IM is cabotegravir (CAB) 600 mg injection (Apretude, GlaxoSmithKline)
There is an important distinction: Daily oral PrEP with F/TDF is recommended to prevent HIV infection among all people at risk through sex or injection drug use. Daily oral PrEP with F/TAF is recommended to prevent HIV infection among people at risk through sex, excluding people at risk through receptive vaginal sex, the CDC notes.
The cost-effectiveness of the injection remains a potential issue, Dr. Hendrix said. On the other hand, “cost-effectiveness goes out the window if there is no adherence.”
An active pipeline
There are 24 new PrEP products in development, as well as 24 other multipurpose prevention technologies (MPTs), which are combination products containing PrEP and one or two other medications.
These 48 products include 28 unique antiviral and contraceptive drugs and 12 delivery methods or formulations. “Why so many?” Dr. Hendrix asked. “Many will not make it through development.”
Pills that include HIV PrEP and contraception or PrEP and sexually transmitted infection (STI) treatment are being evaluated, for example. “HIV risk, pregnancy risk, and other viral STIs overlap. Ideally, you can have one target for all three. That would increase efficiency of dosing and adherence,” Dr. Hendrix said.
Dual prevention pills (DPPs) hypothetically provide HIV PrEP and contraception better than either product alone, Dr. Hendrix said. Plans are to market them as family planning or women’s health products to avoid any stigma or distrust associated with HIV PrEP. An initial rollout is planned in 2024 in sub-Saharan Africa where the unmet need is highest, he added.
“Imagine how effective this could be in women in the United States,” Dr. Hendrix said. “My hope is fourth-quarter 2024” availability in the United States.
A way to prevent STIs and HIV in an all-in-one product “would be terrific,” Dr. Hendrix said.
“I think we’re going to see a lot more innovation going in that direction. The pill is close. The other things are going to be further off because the regulatory pathway is a little more complicated.”
Longer lasting protection?
All of the innovations have gone one of two directions, Dr. Hendrix said. One direction is to make PrEP even longer acting, “so that you have even less to worry [about] in terms of adherence.”
Going forward, “most of the focus has all been on continuously acting or long-active PrEP. It’s getting longer and longer: We’ve got 2 months, and they’re looking at a 6-month subcutaneous injection,” Dr. Hendrix said. The investigational agent lenacapavir is in development as PrEP, as well as for HIV treatment.
“This could get us from 2 to 6 months,” Dr. Hendrix said.
Some of the subcutaneous implants look as if they could provide PrEP for up to 12 months, he added. “An implant could also avoid peaks and troughs with bi-monthly injections.”
On-demand PrEP
The other direction is on-demand. “This is for the folks that don’t want drug in their body all the time. They only want it when they need it. And a twist on that ... is actually using products that are already used with sex now but medicating them.”
On-demand rectal options include a medicated douche and a fast-dissolving insert or suppository.
Fast-dissolving vaginal inserts are also in development. “These inserts are small, easy to store, inexpensive, and possibly inapparent to a partner,” Dr. Hendrix said.
Phase 2 studies will need to determine if these products “fit into folks’ active sex lives,” he said. “There’s still a need for human-friendly, human-designed products.”
A rectal microbicide that got as far as Phase 2 research provides a cautionary tale. The concentrations and the biology worked fine, Dr. Hendrix said. “It was a gel with an applicator, and it just was not liked by the folks in the study.” He added, “Your adherence is going to be in the tank if you’ve got a product that people don’t like to use.”
‘Extremely excited’
Asked for her perspective on Dr. Hendrix’s presentation, session moderator Rasheeta D. Chandler, PhD, RN, an associate professor at the Nell Hodgson Woodruff School of Nursing at Emory University, Atlanta, said: “I am extremely excited, because I work with cisgender women, particularly with underserved women and women of color, and there’s a tendency to focus on men who have sex with men.”
“I understand, because they are the population that is most affected, but Black women are also extremely affected by this disease,” Dr. Chandler told this news organization.
Dr. Chandler applauded Dr. Hendrix for addressing women’s health needs as well and not treating PrEP in women “as an afterthought.”
“Finally, our voices are being heard that [PrEP] should be equitable across all different types of individuals who identify differently in a sexual context,” Dr. Chandler said.
More work is warranted to evaluate PrEP in other populations, including transgender men and individuals who inject drugs, Dr. Hendrix said.
For more information and updates on HIV PrEP and MPTs, visit the website of the nonprofit AIDS Vaccine Advocacy Coalition.
Dr. Hendrix has disclosed receiving research grants from Gilead and Merck. Dr. Chandler has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TAMPA – Pre-exposure prophylaxis (PrEP) has shown to be effective in many clinical and real-world studies, but concerns remain, according to research presented at the annual meeting of the Association of Nurses in AIDS Care (ANAC).
Only about 20% of people who could benefit from PrEP use the preventative medication, for example. Another concern is adherence, as regular use generally drops off over time, rarely lasting more than a few months for most people.
Furthermore, most studies to date evaluated safety and effectiveness of PrEP options among men who have sex with men. Now the focus is increasing on other populations, including women at risk of HIV exposure.
Researchers working on new forms and formulations of PrEP are looking for ways to address those challenges.
said Craig W. Hendrix, MD, professor and director of the Division of Clinical Pharmacology at Johns Hopkins University School of Medicine, Baltimore.
“What I hear a lot of folks say [is] there are two or three options for PrEP, so why do we need more? We need choices that fit into a broader range of lifestyles,” Dr. Hendrix said.
For example, a medically fortified douche containing PrEP might be more likely to be used by people who use a douche before or after sex on a regular basis. This is called a “behaviorally congruent” strategy, Dr. Hendrix said.
In addition to a medical douche, formulations designed to continuously deliver PrEP, such as a subdermal implant, are in the works as well.
Another option for women, the dapivirine vaginal ring, is available internationally but not in the United States. “It was withdrawn from [Food and Drug Administration] consideration by the sponsor. I think it’s a huge loss not to have that,” Dr. Hendrix said.
During development, “frequent expulsions forced reformulation to a less stiff ring,” Dr. Hendrix said. “I don’t imagine that’s terrific, but it shows how important it is to have something that fits the anatomy and the lifestyle.”
“Currently, we have in the U.S. three licensed, really terrific options for PrEP, and they’re all for men that have sex with men and transgender women,” Dr. Hendrix said.
Three current options
The three current PrEP regimens in the United States often go by their abbreviations: F/TDF, F/TAF, and CAB-IM.
- F/TDF is emtricitabine (F) 200 mg in combination with tenofovir disoproxil fumarate (TDF) 300 mg (Truvada, Gilead or generics)
- F/TAF is emtricitabine (F) 200 mg in combination with tenofovir alafenamide (TAF) 25 mg (Descovy, Gilead)
- CAB-IM is cabotegravir (CAB) 600 mg injection (Apretude, GlaxoSmithKline)
There is an important distinction: Daily oral PrEP with F/TDF is recommended to prevent HIV infection among all people at risk through sex or injection drug use. Daily oral PrEP with F/TAF is recommended to prevent HIV infection among people at risk through sex, excluding people at risk through receptive vaginal sex, the CDC notes.
The cost-effectiveness of the injection remains a potential issue, Dr. Hendrix said. On the other hand, “cost-effectiveness goes out the window if there is no adherence.”
An active pipeline
There are 24 new PrEP products in development, as well as 24 other multipurpose prevention technologies (MPTs), which are combination products containing PrEP and one or two other medications.
These 48 products include 28 unique antiviral and contraceptive drugs and 12 delivery methods or formulations. “Why so many?” Dr. Hendrix asked. “Many will not make it through development.”
Pills that include HIV PrEP and contraception or PrEP and sexually transmitted infection (STI) treatment are being evaluated, for example. “HIV risk, pregnancy risk, and other viral STIs overlap. Ideally, you can have one target for all three. That would increase efficiency of dosing and adherence,” Dr. Hendrix said.
Dual prevention pills (DPPs) hypothetically provide HIV PrEP and contraception better than either product alone, Dr. Hendrix said. Plans are to market them as family planning or women’s health products to avoid any stigma or distrust associated with HIV PrEP. An initial rollout is planned in 2024 in sub-Saharan Africa where the unmet need is highest, he added.
“Imagine how effective this could be in women in the United States,” Dr. Hendrix said. “My hope is fourth-quarter 2024” availability in the United States.
A way to prevent STIs and HIV in an all-in-one product “would be terrific,” Dr. Hendrix said.
“I think we’re going to see a lot more innovation going in that direction. The pill is close. The other things are going to be further off because the regulatory pathway is a little more complicated.”
Longer lasting protection?
All of the innovations have gone one of two directions, Dr. Hendrix said. One direction is to make PrEP even longer acting, “so that you have even less to worry [about] in terms of adherence.”
Going forward, “most of the focus has all been on continuously acting or long-active PrEP. It’s getting longer and longer: We’ve got 2 months, and they’re looking at a 6-month subcutaneous injection,” Dr. Hendrix said. The investigational agent lenacapavir is in development as PrEP, as well as for HIV treatment.
“This could get us from 2 to 6 months,” Dr. Hendrix said.
Some of the subcutaneous implants look as if they could provide PrEP for up to 12 months, he added. “An implant could also avoid peaks and troughs with bi-monthly injections.”
On-demand PrEP
The other direction is on-demand. “This is for the folks that don’t want drug in their body all the time. They only want it when they need it. And a twist on that ... is actually using products that are already used with sex now but medicating them.”
On-demand rectal options include a medicated douche and a fast-dissolving insert or suppository.
Fast-dissolving vaginal inserts are also in development. “These inserts are small, easy to store, inexpensive, and possibly inapparent to a partner,” Dr. Hendrix said.
Phase 2 studies will need to determine if these products “fit into folks’ active sex lives,” he said. “There’s still a need for human-friendly, human-designed products.”
A rectal microbicide that got as far as Phase 2 research provides a cautionary tale. The concentrations and the biology worked fine, Dr. Hendrix said. “It was a gel with an applicator, and it just was not liked by the folks in the study.” He added, “Your adherence is going to be in the tank if you’ve got a product that people don’t like to use.”
‘Extremely excited’
Asked for her perspective on Dr. Hendrix’s presentation, session moderator Rasheeta D. Chandler, PhD, RN, an associate professor at the Nell Hodgson Woodruff School of Nursing at Emory University, Atlanta, said: “I am extremely excited, because I work with cisgender women, particularly with underserved women and women of color, and there’s a tendency to focus on men who have sex with men.”
“I understand, because they are the population that is most affected, but Black women are also extremely affected by this disease,” Dr. Chandler told this news organization.
Dr. Chandler applauded Dr. Hendrix for addressing women’s health needs as well and not treating PrEP in women “as an afterthought.”
“Finally, our voices are being heard that [PrEP] should be equitable across all different types of individuals who identify differently in a sexual context,” Dr. Chandler said.
More work is warranted to evaluate PrEP in other populations, including transgender men and individuals who inject drugs, Dr. Hendrix said.
For more information and updates on HIV PrEP and MPTs, visit the website of the nonprofit AIDS Vaccine Advocacy Coalition.
Dr. Hendrix has disclosed receiving research grants from Gilead and Merck. Dr. Chandler has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ANAC 2022
People living with HIV are a model population for vaccination
TAMPA – People living with HIV (PLWH) were more likely than other populations to get vaccinated for flu and COVID-19, to seek reputable sources of information, and to be connected through essential community organizations that share essential health and wellness information, according to the results of a large survey.
PLWH, therefore, would have been an ideal model population for creating and disseminating effective messaging around COVID-19 immunizations earlier in the pandemic, said Kathleen Gallagher, MPH, an epidemiologist, researcher, and health services administrator at the Patient Advocate Foundation.
The PLWH community can still offer valuable insights into effective ways to reach out to people, to disseminate correct information, and to link people with resources, Ms. Gallagher said during a poster presentation at the annual meeting of the Association of Nurses in AIDS Care (ANAC).
Local, community-based organizations “are the people that these individuals trust, they are people entrenched in their community, and they have existing relationships with them in terms of getting vaccinated and listening to their concerns,” Ms. Gallagher said.
“It’s a missed opportunity.”
A highly compliant group
The July 2021 survey of 271 PLWH was part of a larger, longitudinal survey of 1,400 people with any chronic illness asked about attitudes and barriers to vaccination. The PLWH population was important to focus on, the researchers note, because they could be potentially high risk for more serious COVID-19 outcomes.
The PLWH group was 81% White and 90% male, and 83% were age 56 or older. In addition, 86% had an annual household income below $48,000.
Ninety-three percent of the PLWH group had had flu vaccination in the prior 3 years and received at least one COVID-19 vaccination.
Unable vs. unwilling to vaccinate
Ms. Gallagher and colleagues found 12 people (4%) in the PLWH group did not get vaccinated against COVID-19. It’s a small number, “so you have to take this with a grain of salt,” she said. “But we asked them why they were hesitant. They either were unable or unwilling – and the unable part is not surprising.”
Those who were unable to get vaccinated were either homebound or had concerns about being in a clinic where they could be exposed to COVID while waiting to get the vaccine.
“And then there were some who were just not willing” to get vaccinated, Ms. Gallagher said. She added most cited vaccine safety concerns and “a lot of the misinformation or confusing information around efficacy.”
Trusted information sources
Although people reported getting COVID-19 vaccine information from multiple sources, including online and from television, 64% or nearly two-thirds sought information from their doctors or health care teams.
In fact, doctors emerged as the most trusted source, as indicated by 72% of PLWH.
“I was a little surprised that doctors scored so highly because, sometimes in other cohorts that we looked at, it wasn’t the case,” Ms. Gallagher said. However, she added, a lot of PLWH “have a very strong trust bond with their provider because this is a very personal, very sensitive diagnosis.”
How did social media score? “A whopping 1%,” she said. “So at least this was a savvy group, and they realized that that was not the place to go for vaccination information.”
Overcoming barriers
A lack of vaccine availability at the time of their appointment was the number one barrier to immunization. Also, a small number of people said knowing someone who had an adverse reaction to COVID-19 vaccination was a barrier for them. Ms. Gallagher explained that, by definition in the survey, an adverse reaction to vaccination had to be serious enough to drive people to seek medical care.
When asked to comment on the poster, Andrew Komensky, RN, told this news organization that he found the results “interesting, because I’m an infection preventionist, in addition to being an HIV nurse.” He is director of infection prevention and control at CharterCARE Health Partners, Providence, R.I.
Mr. Komensky said he was surprised that a high proportion of PLWH cited their doctor – and not their nurse – as the most trusted source of information. “In my experience in COVID care ... it was a nursing staff who had most of the contact with patients, who did most of the education, and provided most of the information surrounding vaccination and potential side effects.”
It made sense to Mr. Komensky that the PLWH population would be compliant with vaccinations. “People who are living with HIV do everything they possibly can just to stay healthy.”
A version of this article first appeared on Medscape.com.
TAMPA – People living with HIV (PLWH) were more likely than other populations to get vaccinated for flu and COVID-19, to seek reputable sources of information, and to be connected through essential community organizations that share essential health and wellness information, according to the results of a large survey.
PLWH, therefore, would have been an ideal model population for creating and disseminating effective messaging around COVID-19 immunizations earlier in the pandemic, said Kathleen Gallagher, MPH, an epidemiologist, researcher, and health services administrator at the Patient Advocate Foundation.
The PLWH community can still offer valuable insights into effective ways to reach out to people, to disseminate correct information, and to link people with resources, Ms. Gallagher said during a poster presentation at the annual meeting of the Association of Nurses in AIDS Care (ANAC).
Local, community-based organizations “are the people that these individuals trust, they are people entrenched in their community, and they have existing relationships with them in terms of getting vaccinated and listening to their concerns,” Ms. Gallagher said.
“It’s a missed opportunity.”
A highly compliant group
The July 2021 survey of 271 PLWH was part of a larger, longitudinal survey of 1,400 people with any chronic illness asked about attitudes and barriers to vaccination. The PLWH population was important to focus on, the researchers note, because they could be potentially high risk for more serious COVID-19 outcomes.
The PLWH group was 81% White and 90% male, and 83% were age 56 or older. In addition, 86% had an annual household income below $48,000.
Ninety-three percent of the PLWH group had had flu vaccination in the prior 3 years and received at least one COVID-19 vaccination.
Unable vs. unwilling to vaccinate
Ms. Gallagher and colleagues found 12 people (4%) in the PLWH group did not get vaccinated against COVID-19. It’s a small number, “so you have to take this with a grain of salt,” she said. “But we asked them why they were hesitant. They either were unable or unwilling – and the unable part is not surprising.”
Those who were unable to get vaccinated were either homebound or had concerns about being in a clinic where they could be exposed to COVID while waiting to get the vaccine.
“And then there were some who were just not willing” to get vaccinated, Ms. Gallagher said. She added most cited vaccine safety concerns and “a lot of the misinformation or confusing information around efficacy.”
Trusted information sources
Although people reported getting COVID-19 vaccine information from multiple sources, including online and from television, 64% or nearly two-thirds sought information from their doctors or health care teams.
In fact, doctors emerged as the most trusted source, as indicated by 72% of PLWH.
“I was a little surprised that doctors scored so highly because, sometimes in other cohorts that we looked at, it wasn’t the case,” Ms. Gallagher said. However, she added, a lot of PLWH “have a very strong trust bond with their provider because this is a very personal, very sensitive diagnosis.”
How did social media score? “A whopping 1%,” she said. “So at least this was a savvy group, and they realized that that was not the place to go for vaccination information.”
Overcoming barriers
A lack of vaccine availability at the time of their appointment was the number one barrier to immunization. Also, a small number of people said knowing someone who had an adverse reaction to COVID-19 vaccination was a barrier for them. Ms. Gallagher explained that, by definition in the survey, an adverse reaction to vaccination had to be serious enough to drive people to seek medical care.
When asked to comment on the poster, Andrew Komensky, RN, told this news organization that he found the results “interesting, because I’m an infection preventionist, in addition to being an HIV nurse.” He is director of infection prevention and control at CharterCARE Health Partners, Providence, R.I.
Mr. Komensky said he was surprised that a high proportion of PLWH cited their doctor – and not their nurse – as the most trusted source of information. “In my experience in COVID care ... it was a nursing staff who had most of the contact with patients, who did most of the education, and provided most of the information surrounding vaccination and potential side effects.”
It made sense to Mr. Komensky that the PLWH population would be compliant with vaccinations. “People who are living with HIV do everything they possibly can just to stay healthy.”
A version of this article first appeared on Medscape.com.
TAMPA – People living with HIV (PLWH) were more likely than other populations to get vaccinated for flu and COVID-19, to seek reputable sources of information, and to be connected through essential community organizations that share essential health and wellness information, according to the results of a large survey.
PLWH, therefore, would have been an ideal model population for creating and disseminating effective messaging around COVID-19 immunizations earlier in the pandemic, said Kathleen Gallagher, MPH, an epidemiologist, researcher, and health services administrator at the Patient Advocate Foundation.
The PLWH community can still offer valuable insights into effective ways to reach out to people, to disseminate correct information, and to link people with resources, Ms. Gallagher said during a poster presentation at the annual meeting of the Association of Nurses in AIDS Care (ANAC).
Local, community-based organizations “are the people that these individuals trust, they are people entrenched in their community, and they have existing relationships with them in terms of getting vaccinated and listening to their concerns,” Ms. Gallagher said.
“It’s a missed opportunity.”
A highly compliant group
The July 2021 survey of 271 PLWH was part of a larger, longitudinal survey of 1,400 people with any chronic illness asked about attitudes and barriers to vaccination. The PLWH population was important to focus on, the researchers note, because they could be potentially high risk for more serious COVID-19 outcomes.
The PLWH group was 81% White and 90% male, and 83% were age 56 or older. In addition, 86% had an annual household income below $48,000.
Ninety-three percent of the PLWH group had had flu vaccination in the prior 3 years and received at least one COVID-19 vaccination.
Unable vs. unwilling to vaccinate
Ms. Gallagher and colleagues found 12 people (4%) in the PLWH group did not get vaccinated against COVID-19. It’s a small number, “so you have to take this with a grain of salt,” she said. “But we asked them why they were hesitant. They either were unable or unwilling – and the unable part is not surprising.”
Those who were unable to get vaccinated were either homebound or had concerns about being in a clinic where they could be exposed to COVID while waiting to get the vaccine.
“And then there were some who were just not willing” to get vaccinated, Ms. Gallagher said. She added most cited vaccine safety concerns and “a lot of the misinformation or confusing information around efficacy.”
Trusted information sources
Although people reported getting COVID-19 vaccine information from multiple sources, including online and from television, 64% or nearly two-thirds sought information from their doctors or health care teams.
In fact, doctors emerged as the most trusted source, as indicated by 72% of PLWH.
“I was a little surprised that doctors scored so highly because, sometimes in other cohorts that we looked at, it wasn’t the case,” Ms. Gallagher said. However, she added, a lot of PLWH “have a very strong trust bond with their provider because this is a very personal, very sensitive diagnosis.”
How did social media score? “A whopping 1%,” she said. “So at least this was a savvy group, and they realized that that was not the place to go for vaccination information.”
Overcoming barriers
A lack of vaccine availability at the time of their appointment was the number one barrier to immunization. Also, a small number of people said knowing someone who had an adverse reaction to COVID-19 vaccination was a barrier for them. Ms. Gallagher explained that, by definition in the survey, an adverse reaction to vaccination had to be serious enough to drive people to seek medical care.
When asked to comment on the poster, Andrew Komensky, RN, told this news organization that he found the results “interesting, because I’m an infection preventionist, in addition to being an HIV nurse.” He is director of infection prevention and control at CharterCARE Health Partners, Providence, R.I.
Mr. Komensky said he was surprised that a high proportion of PLWH cited their doctor – and not their nurse – as the most trusted source of information. “In my experience in COVID care ... it was a nursing staff who had most of the contact with patients, who did most of the education, and provided most of the information surrounding vaccination and potential side effects.”
It made sense to Mr. Komensky that the PLWH population would be compliant with vaccinations. “People who are living with HIV do everything they possibly can just to stay healthy.”
A version of this article first appeared on Medscape.com.
FROM ANAC 2022