Pharmacology

The Food and Drug Administration on Aug. 9 authorized intradermal administration of the Jynneos vaccine for the treatment of monkeypox. The process, approved specifically for high-risk patients, was passed under the administration’s Emergency Use Authorization. It follows the decision on Aug. 4 by the U.S. Department of Health and Human Services to declare monkeypox a public health emergency. Intradermal administration will allow providers to get five doses out of a one-dose vial.

This news organization will update this article as more information becomes available.

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

The Food and Drug Administration on Aug. 9 authorized intradermal administration of the Jynneos vaccine for the treatment of monkeypox. The process, approved specifically for high-risk patients, was passed under the administration’s Emergency Use Authorization. It follows the decision on Aug. 4 by the U.S. Department of Health and Human Services to declare monkeypox a public health emergency. Intradermal administration will allow providers to get five doses out of a one-dose vial.

This news organization will update this article as more information becomes available.

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

The Food and Drug Administration on Aug. 9 authorized intradermal administration of the Jynneos vaccine for the treatment of monkeypox. The process, approved specifically for high-risk patients, was passed under the administration’s Emergency Use Authorization. It follows the decision on Aug. 4 by the U.S. Department of Health and Human Services to declare monkeypox a public health emergency. Intradermal administration will allow providers to get five doses out of a one-dose vial.

This news organization will update this article as more information becomes available.

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

Hormone therapy remains a topic for debate, but a constant in the 2 decades since the Women’s Health Initiative has been the demonstrated effectiveness for relief of vasomotor symptoms and reduction of fracture risk in menopausal women, according to the latest hormone therapy position statement of the North American Menopause Society.

“Healthcare professionals caring for menopausal women should understand the basic concepts of relative risk and absolute risk,” wrote Stephanie S. Faubion, MD, director of the Mayo Clinic Center for Women’s Health and medical director of NAMS, and members of the NAMS 2022 Hormone Therapy Position Statement Advisory Panel in Menopause.

The authors noted that the risks of hormone therapy vary considerably based on type, dose, duration, route of administration, timing of the start of therapy, and whether or not a progestogen is included.

The 2022 statement was commissioned to review new literature and identify the strength of recommendations and quality of evidence since the previous statement in 2017.

The current statement represents not so much a practice-changing update, “but rather that the literature has filled out in some areas,” Dr. Faubion said in an interview. “The recommendations overall haven’t changed,” she said. “The position statement reiterates that hormone therapy, which is significantly underutilized, remains a safe and effective treatment for menopause symptoms, which remain undertreated, with the benefits outweighing the risks for most healthy women who are within 10 years of menopause onset and under the age of 60 years,” she emphasized. “Individualizing therapy is key to maximizing benefits and minimizing risks,” she added.

Overall, the authors confirmed that hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM), and has been shown to prevent bone loss and fracture. The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used.

Risks and benefits should be stratified by age and time since the start of menopause, according to the statement.

For women younger than 60 years or within 10 years of the onset of menopause who have no contraindications, the potential benefits outweigh the risks in most cases for use of hormone therapy to manage vasomotor symptoms and to help prevent bone loss and reduce fracture risk.

For women who begin hormone therapy more than 10 or 20 years from the start of menopause, or who are aged 60 years and older, the risk-benefit ratio may be less favorable because of the increased absolute risk of coronary heart disease, stroke, venous thromboembolism, and dementia. However, strategies such as lower doses and transdermal administration may reduce this risk, according to the statement.

The authors continue to recommend that longer durations of hormone therapy be for documented indications, such as VMS relief, and that patients on longer duration of therapy be reassessed periodically as part of a shared decision-making process. Women with persistent VMS or quality of life issues, or those at risk for osteoporosis, may continue hormone therapy beyond age 60 or 65 years after appropriate evaluation and risk-benefit counseling.

Women with ongoing GSM without indications for systemic therapy whose GSM persists after over-the-counter therapies may try low-dose vaginal estrogen or other nonestrogen therapies regardless of age and for an extended duration if needed, according to the statement.
 

Challenges, research gaps, and goals

“Barriers to the use of hormone therapy include lack of access to high quality care,” Dr. Faubion said in an interview. The NAMS website, menopause.org, features an option to search for a NAMS-certified provider by ZIP code, she noted.

“Coverage of hormone therapy is highly variable and depends on the insurance company, but most women have access to one form or another with insurance coverage,” she said. “We need to continue to advocate for adequate coverage of menopause symptom treatments, including hormone therapy, so that women’s symptoms – which can significantly affect quality of life – are adequately managed.

“Additional research is needed on the thrombotic risk (venous thromboembolism, pulmonary embolism, and stroke) of oral versus transdermal therapies (including different formulations, doses, and durations of therapy),” Dr. Faubion told this news organization. “More clinical trial data are needed to confirm or refute the potential beneficial effects of hormone therapy on coronary heart disease and all-cause mortality when initiated in perimenopause or early postmenopause,” she said.

Other areas for research include “the breast effects of different estrogen preparations, including the role for selective estrogen receptor modulator (SERM) and tissue selective estrogen complex therapies, optimal progestogen or SERM regimens to prevent endometrial hyperplasia, the relationship between vasomotor symptoms and the risk for heart disease and cognitive changes, and the risks of premature ovarian insufficiency,” Dr. Faubion emphasized.

Looking ahead, “Studies are needed on the effects of longer use of low-dose vaginal estrogen therapy after breast or endometrial cancer, extended use of hormone therapy in women who are early initiators, improved tools to personalize or individualize benefits and risks of hormone therapy, and the role of aging and genetics,” said Dr. Faubion. Other areas for further research include “the long-term benefits and risks on women’s health of lifestyle modification or complementary or nonhormone therapies, if chosen in addition to or over hormone therapy for vasomotor symptoms, bone health, and cardiovascular disease risk reduction,” she added.

The complete statement was published in Menopause: The Journal of the North American Menopause Society.

The position statement received no outside funding. The authors had no financial conflicts to disclose.

Hormone therapy remains a topic for debate, but a constant in the 2 decades since the Women’s Health Initiative has been the demonstrated effectiveness for relief of vasomotor symptoms and reduction of fracture risk in menopausal women, according to the latest hormone therapy position statement of the North American Menopause Society.

“Healthcare professionals caring for menopausal women should understand the basic concepts of relative risk and absolute risk,” wrote Stephanie S. Faubion, MD, director of the Mayo Clinic Center for Women’s Health and medical director of NAMS, and members of the NAMS 2022 Hormone Therapy Position Statement Advisory Panel in Menopause.

The authors noted that the risks of hormone therapy vary considerably based on type, dose, duration, route of administration, timing of the start of therapy, and whether or not a progestogen is included.

The 2022 statement was commissioned to review new literature and identify the strength of recommendations and quality of evidence since the previous statement in 2017.

The current statement represents not so much a practice-changing update, “but rather that the literature has filled out in some areas,” Dr. Faubion said in an interview. “The recommendations overall haven’t changed,” she said. “The position statement reiterates that hormone therapy, which is significantly underutilized, remains a safe and effective treatment for menopause symptoms, which remain undertreated, with the benefits outweighing the risks for most healthy women who are within 10 years of menopause onset and under the age of 60 years,” she emphasized. “Individualizing therapy is key to maximizing benefits and minimizing risks,” she added.

Overall, the authors confirmed that hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM), and has been shown to prevent bone loss and fracture. The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used.

Risks and benefits should be stratified by age and time since the start of menopause, according to the statement.

For women younger than 60 years or within 10 years of the onset of menopause who have no contraindications, the potential benefits outweigh the risks in most cases for use of hormone therapy to manage vasomotor symptoms and to help prevent bone loss and reduce fracture risk.

For women who begin hormone therapy more than 10 or 20 years from the start of menopause, or who are aged 60 years and older, the risk-benefit ratio may be less favorable because of the increased absolute risk of coronary heart disease, stroke, venous thromboembolism, and dementia. However, strategies such as lower doses and transdermal administration may reduce this risk, according to the statement.

The authors continue to recommend that longer durations of hormone therapy be for documented indications, such as VMS relief, and that patients on longer duration of therapy be reassessed periodically as part of a shared decision-making process. Women with persistent VMS or quality of life issues, or those at risk for osteoporosis, may continue hormone therapy beyond age 60 or 65 years after appropriate evaluation and risk-benefit counseling.

Women with ongoing GSM without indications for systemic therapy whose GSM persists after over-the-counter therapies may try low-dose vaginal estrogen or other nonestrogen therapies regardless of age and for an extended duration if needed, according to the statement.
 

Challenges, research gaps, and goals

“Barriers to the use of hormone therapy include lack of access to high quality care,” Dr. Faubion said in an interview. The NAMS website, menopause.org, features an option to search for a NAMS-certified provider by ZIP code, she noted.

“Coverage of hormone therapy is highly variable and depends on the insurance company, but most women have access to one form or another with insurance coverage,” she said. “We need to continue to advocate for adequate coverage of menopause symptom treatments, including hormone therapy, so that women’s symptoms – which can significantly affect quality of life – are adequately managed.

“Additional research is needed on the thrombotic risk (venous thromboembolism, pulmonary embolism, and stroke) of oral versus transdermal therapies (including different formulations, doses, and durations of therapy),” Dr. Faubion told this news organization. “More clinical trial data are needed to confirm or refute the potential beneficial effects of hormone therapy on coronary heart disease and all-cause mortality when initiated in perimenopause or early postmenopause,” she said.

Other areas for research include “the breast effects of different estrogen preparations, including the role for selective estrogen receptor modulator (SERM) and tissue selective estrogen complex therapies, optimal progestogen or SERM regimens to prevent endometrial hyperplasia, the relationship between vasomotor symptoms and the risk for heart disease and cognitive changes, and the risks of premature ovarian insufficiency,” Dr. Faubion emphasized.

Looking ahead, “Studies are needed on the effects of longer use of low-dose vaginal estrogen therapy after breast or endometrial cancer, extended use of hormone therapy in women who are early initiators, improved tools to personalize or individualize benefits and risks of hormone therapy, and the role of aging and genetics,” said Dr. Faubion. Other areas for further research include “the long-term benefits and risks on women’s health of lifestyle modification or complementary or nonhormone therapies, if chosen in addition to or over hormone therapy for vasomotor symptoms, bone health, and cardiovascular disease risk reduction,” she added.

The complete statement was published in Menopause: The Journal of the North American Menopause Society.

The position statement received no outside funding. The authors had no financial conflicts to disclose.

Hormone therapy remains a topic for debate, but a constant in the 2 decades since the Women’s Health Initiative has been the demonstrated effectiveness for relief of vasomotor symptoms and reduction of fracture risk in menopausal women, according to the latest hormone therapy position statement of the North American Menopause Society.

“Healthcare professionals caring for menopausal women should understand the basic concepts of relative risk and absolute risk,” wrote Stephanie S. Faubion, MD, director of the Mayo Clinic Center for Women’s Health and medical director of NAMS, and members of the NAMS 2022 Hormone Therapy Position Statement Advisory Panel in Menopause.

The authors noted that the risks of hormone therapy vary considerably based on type, dose, duration, route of administration, timing of the start of therapy, and whether or not a progestogen is included.

The 2022 statement was commissioned to review new literature and identify the strength of recommendations and quality of evidence since the previous statement in 2017.

The current statement represents not so much a practice-changing update, “but rather that the literature has filled out in some areas,” Dr. Faubion said in an interview. “The recommendations overall haven’t changed,” she said. “The position statement reiterates that hormone therapy, which is significantly underutilized, remains a safe and effective treatment for menopause symptoms, which remain undertreated, with the benefits outweighing the risks for most healthy women who are within 10 years of menopause onset and under the age of 60 years,” she emphasized. “Individualizing therapy is key to maximizing benefits and minimizing risks,” she added.

Overall, the authors confirmed that hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM), and has been shown to prevent bone loss and fracture. The risks of hormone therapy differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used.

Risks and benefits should be stratified by age and time since the start of menopause, according to the statement.

For women younger than 60 years or within 10 years of the onset of menopause who have no contraindications, the potential benefits outweigh the risks in most cases for use of hormone therapy to manage vasomotor symptoms and to help prevent bone loss and reduce fracture risk.

For women who begin hormone therapy more than 10 or 20 years from the start of menopause, or who are aged 60 years and older, the risk-benefit ratio may be less favorable because of the increased absolute risk of coronary heart disease, stroke, venous thromboembolism, and dementia. However, strategies such as lower doses and transdermal administration may reduce this risk, according to the statement.

The authors continue to recommend that longer durations of hormone therapy be for documented indications, such as VMS relief, and that patients on longer duration of therapy be reassessed periodically as part of a shared decision-making process. Women with persistent VMS or quality of life issues, or those at risk for osteoporosis, may continue hormone therapy beyond age 60 or 65 years after appropriate evaluation and risk-benefit counseling.

Women with ongoing GSM without indications for systemic therapy whose GSM persists after over-the-counter therapies may try low-dose vaginal estrogen or other nonestrogen therapies regardless of age and for an extended duration if needed, according to the statement.
 

Challenges, research gaps, and goals

“Barriers to the use of hormone therapy include lack of access to high quality care,” Dr. Faubion said in an interview. The NAMS website, menopause.org, features an option to search for a NAMS-certified provider by ZIP code, she noted.

“Coverage of hormone therapy is highly variable and depends on the insurance company, but most women have access to one form or another with insurance coverage,” she said. “We need to continue to advocate for adequate coverage of menopause symptom treatments, including hormone therapy, so that women’s symptoms – which can significantly affect quality of life – are adequately managed.

“Additional research is needed on the thrombotic risk (venous thromboembolism, pulmonary embolism, and stroke) of oral versus transdermal therapies (including different formulations, doses, and durations of therapy),” Dr. Faubion told this news organization. “More clinical trial data are needed to confirm or refute the potential beneficial effects of hormone therapy on coronary heart disease and all-cause mortality when initiated in perimenopause or early postmenopause,” she said.

Other areas for research include “the breast effects of different estrogen preparations, including the role for selective estrogen receptor modulator (SERM) and tissue selective estrogen complex therapies, optimal progestogen or SERM regimens to prevent endometrial hyperplasia, the relationship between vasomotor symptoms and the risk for heart disease and cognitive changes, and the risks of premature ovarian insufficiency,” Dr. Faubion emphasized.

Looking ahead, “Studies are needed on the effects of longer use of low-dose vaginal estrogen therapy after breast or endometrial cancer, extended use of hormone therapy in women who are early initiators, improved tools to personalize or individualize benefits and risks of hormone therapy, and the role of aging and genetics,” said Dr. Faubion. Other areas for further research include “the long-term benefits and risks on women’s health of lifestyle modification or complementary or nonhormone therapies, if chosen in addition to or over hormone therapy for vasomotor symptoms, bone health, and cardiovascular disease risk reduction,” she added.

The complete statement was published in Menopause: The Journal of the North American Menopause Society.

The position statement received no outside funding. The authors had no financial conflicts to disclose.

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

Topical ruxolitinib appears to quickly relieve itch in Black patients with atopic dermatitis (AD), an industry-sponsored analysis of pooled data from two studies suggests.

“Ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black or African American patients with AD and was well tolerated,” the study authors wrote in a poster presented at the annual meeting of the Society for Investigative Dermatology.

AD can behave differently in different racial groups and can be especially bothersome in Black patients. AD has a prevalence of about 20% in Black children and 5%-10% in Black adults. Black children are roughly twice as likely to be diagnosed with AD, and to have severe AD, than White children, according to the authors.

Lead author Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, and colleagues used pooled data from two identically designed phase 3 studies to describe the effects of the cream formulation of the Janus kinase (JAK) 1 and JAK 2 inhibitor ruxolitinib on itch in Black patients.

Topical ruxolitinib (Opzelura), 1.5%, was approved last September for treating AD in non-immunocompromised patients with mild to moderate AD, ages 12 years and older. In July 2022, it was approved for the treatment of nonsegmental vitiligo in the same age group.  

FDA approval for AD was based on the results of the TRuE-AD1 and TRuE-AD2 double-blind randomized trials, which enrolled about 1,200 patients over age 12 with AD. These patients included 292 Black teenagers and adults between aged 12-71 years who had AD for 2 years or longer, with an Investigator’s Global Assessment (IGA) score of 2 or 3, with 3%-20% affected body surface area, excluding the scalp.

Of the 292 patients, those in the two treatment groups (n = 231) applied ruxolitinib cream twice a day for 8 weeks (0.75% in 118 patients and 1.5% in 113 patients) and 61 applied the vehicle. They used electronic diaries to record the worst level of itch they had experienced each day, from 0 (no itch) to 10 (worst imaginable itch). The main results were as follows: 

• Mean itch numerical rating scale (NRS) scores at baseline were 5.3 and 5.4 for ruxolitinib cream 0.75% and 1.5%, respectively, and 5.7 for vehicle. Within about 12 hours of first application, mean itch NRS scores dropped –0.6 and –0.7 from baseline among those treated with ruxolitinib cream 0.75% and 1.5%, respectively, compared with –0.2 for those on the vehicle. At day 4, the decreases were –1.4 and –1.6 for ruxolitinib cream 0.75% and 1.5%, respectively, versus –0.6 for the vehicle (P = .026 and P = .005, respectively, vs. vehicle).
• At day 2, among the 187 patients with a baseline itch NRS score 4 or higher, more patients achieved 4-point or greater itch NRS improvement: 6.1% and 16.4% for ruxolitinib cream 0.75% and 1.5%, respectively versus 0% for vehicle. At day 7, the differences were 15.9% and 26.6% versus 3%, respectively. And by week 8, they increased to 30.1% and 43.2% versus 17.5% (P = .212 and P = .009), respectively.
• At week 2, 19% of patients in the 0.75% formulation group and 19.4% of patients in the 1.5% formulation group, compared with 5.3% in the vehicle group, reported no days of itch on question 1 of the Patient-Oriented Eczema Measure (POEM) questionnaire that evaluated various aspects of the disease over the previous week. By week 8, the differences grew to 34% and 30.8% versus 12.2%, respectively.
• Adverse events, reported by 14.4% and 22.1% of patients on 0.75% and 1.5% ruxolitinib, respectively, and by 32.8% of patients who received the vehicle, were headaches, upper respiratory tract infection, and application site pain.

Ruxolitinib may be an alternative to systemic immunosuppressives

Asked to comment on the results, Amy J. McMichael, MD, professor of dermatology at Wake Forest University School of Medicine, Winston-Salem, N.C., called itch “one of the major life disruptors in atopic dermatitis.”

Providers often assume that patients of different races respond similarly to treatment, but that is not always true, she noted in an email.

“This study proves ruxolitinib’s effectiveness in Black patients, who often have more severe atopic dermatitis signs and symptoms,” said Dr. McMichael, who was not involved in the study. “The fact that atopic dermatitis in patients of color has been singled out to examine efficacy is a great way to show that the findings are not just in those who have thinner plaques and potentially less longstanding thickening of the skin from scratching (lichenification),” she added.

Dr. McMichael welcomed the lack of systemic side effects and quick relief of itch with this treatment, noting that the effect on itch “is rare with other treatments and extremely rare with other topical medications.”

The effect of topical ruxolitinib on pruritus “was interesting and surprising because very few available topical medications can control itch,” she explained. “The strongest topical steroids can help with pruritus, but they have the risk for skin thinning (atrophy),” while topical ruxolitinib is not associated with skin atrophy.

“After topical steroids fail as first-line treatment, it is likely that more patients will be given this topical medication rather than be moved to immunosuppressive systemic medications,” she noted.

All study authors report relevant relationships with Incyte Corporation, which manufactures ruxolitinib and funded the study, and several authors report employment and shareholding interests in the company. Dr. McMichael reports no relevant relationship with the study.

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

Topical ruxolitinib appears to quickly relieve itch in Black patients with atopic dermatitis (AD), an industry-sponsored analysis of pooled data from two studies suggests.

“Ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black or African American patients with AD and was well tolerated,” the study authors wrote in a poster presented at the annual meeting of the Society for Investigative Dermatology.

AD can behave differently in different racial groups and can be especially bothersome in Black patients. AD has a prevalence of about 20% in Black children and 5%-10% in Black adults. Black children are roughly twice as likely to be diagnosed with AD, and to have severe AD, than White children, according to the authors.

Lead author Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, and colleagues used pooled data from two identically designed phase 3 studies to describe the effects of the cream formulation of the Janus kinase (JAK) 1 and JAK 2 inhibitor ruxolitinib on itch in Black patients.

Topical ruxolitinib (Opzelura), 1.5%, was approved last September for treating AD in non-immunocompromised patients with mild to moderate AD, ages 12 years and older. In July 2022, it was approved for the treatment of nonsegmental vitiligo in the same age group.  

FDA approval for AD was based on the results of the TRuE-AD1 and TRuE-AD2 double-blind randomized trials, which enrolled about 1,200 patients over age 12 with AD. These patients included 292 Black teenagers and adults between aged 12-71 years who had AD for 2 years or longer, with an Investigator’s Global Assessment (IGA) score of 2 or 3, with 3%-20% affected body surface area, excluding the scalp.

Of the 292 patients, those in the two treatment groups (n = 231) applied ruxolitinib cream twice a day for 8 weeks (0.75% in 118 patients and 1.5% in 113 patients) and 61 applied the vehicle. They used electronic diaries to record the worst level of itch they had experienced each day, from 0 (no itch) to 10 (worst imaginable itch). The main results were as follows: 

• Mean itch numerical rating scale (NRS) scores at baseline were 5.3 and 5.4 for ruxolitinib cream 0.75% and 1.5%, respectively, and 5.7 for vehicle. Within about 12 hours of first application, mean itch NRS scores dropped –0.6 and –0.7 from baseline among those treated with ruxolitinib cream 0.75% and 1.5%, respectively, compared with –0.2 for those on the vehicle. At day 4, the decreases were –1.4 and –1.6 for ruxolitinib cream 0.75% and 1.5%, respectively, versus –0.6 for the vehicle (P = .026 and P = .005, respectively, vs. vehicle).
• At day 2, among the 187 patients with a baseline itch NRS score 4 or higher, more patients achieved 4-point or greater itch NRS improvement: 6.1% and 16.4% for ruxolitinib cream 0.75% and 1.5%, respectively versus 0% for vehicle. At day 7, the differences were 15.9% and 26.6% versus 3%, respectively. And by week 8, they increased to 30.1% and 43.2% versus 17.5% (P = .212 and P = .009), respectively.
• At week 2, 19% of patients in the 0.75% formulation group and 19.4% of patients in the 1.5% formulation group, compared with 5.3% in the vehicle group, reported no days of itch on question 1 of the Patient-Oriented Eczema Measure (POEM) questionnaire that evaluated various aspects of the disease over the previous week. By week 8, the differences grew to 34% and 30.8% versus 12.2%, respectively.
• Adverse events, reported by 14.4% and 22.1% of patients on 0.75% and 1.5% ruxolitinib, respectively, and by 32.8% of patients who received the vehicle, were headaches, upper respiratory tract infection, and application site pain.

Ruxolitinib may be an alternative to systemic immunosuppressives

Asked to comment on the results, Amy J. McMichael, MD, professor of dermatology at Wake Forest University School of Medicine, Winston-Salem, N.C., called itch “one of the major life disruptors in atopic dermatitis.”

Providers often assume that patients of different races respond similarly to treatment, but that is not always true, she noted in an email.

“This study proves ruxolitinib’s effectiveness in Black patients, who often have more severe atopic dermatitis signs and symptoms,” said Dr. McMichael, who was not involved in the study. “The fact that atopic dermatitis in patients of color has been singled out to examine efficacy is a great way to show that the findings are not just in those who have thinner plaques and potentially less longstanding thickening of the skin from scratching (lichenification),” she added.

Dr. McMichael welcomed the lack of systemic side effects and quick relief of itch with this treatment, noting that the effect on itch “is rare with other treatments and extremely rare with other topical medications.”

The effect of topical ruxolitinib on pruritus “was interesting and surprising because very few available topical medications can control itch,” she explained. “The strongest topical steroids can help with pruritus, but they have the risk for skin thinning (atrophy),” while topical ruxolitinib is not associated with skin atrophy.

“After topical steroids fail as first-line treatment, it is likely that more patients will be given this topical medication rather than be moved to immunosuppressive systemic medications,” she noted.

All study authors report relevant relationships with Incyte Corporation, which manufactures ruxolitinib and funded the study, and several authors report employment and shareholding interests in the company. Dr. McMichael reports no relevant relationship with the study.

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

Topical ruxolitinib appears to quickly relieve itch in Black patients with atopic dermatitis (AD), an industry-sponsored analysis of pooled data from two studies suggests.

“Ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black or African American patients with AD and was well tolerated,” the study authors wrote in a poster presented at the annual meeting of the Society for Investigative Dermatology.

AD can behave differently in different racial groups and can be especially bothersome in Black patients. AD has a prevalence of about 20% in Black children and 5%-10% in Black adults. Black children are roughly twice as likely to be diagnosed with AD, and to have severe AD, than White children, according to the authors.

Lead author Lawrence F. Eichenfield, MD, professor of dermatology and pediatrics at the University of California, San Diego, and colleagues used pooled data from two identically designed phase 3 studies to describe the effects of the cream formulation of the Janus kinase (JAK) 1 and JAK 2 inhibitor ruxolitinib on itch in Black patients.

Topical ruxolitinib (Opzelura), 1.5%, was approved last September for treating AD in non-immunocompromised patients with mild to moderate AD, ages 12 years and older. In July 2022, it was approved for the treatment of nonsegmental vitiligo in the same age group.  

FDA approval for AD was based on the results of the TRuE-AD1 and TRuE-AD2 double-blind randomized trials, which enrolled about 1,200 patients over age 12 with AD. These patients included 292 Black teenagers and adults between aged 12-71 years who had AD for 2 years or longer, with an Investigator’s Global Assessment (IGA) score of 2 or 3, with 3%-20% affected body surface area, excluding the scalp.

Of the 292 patients, those in the two treatment groups (n = 231) applied ruxolitinib cream twice a day for 8 weeks (0.75% in 118 patients and 1.5% in 113 patients) and 61 applied the vehicle. They used electronic diaries to record the worst level of itch they had experienced each day, from 0 (no itch) to 10 (worst imaginable itch). The main results were as follows: 

• Mean itch numerical rating scale (NRS) scores at baseline were 5.3 and 5.4 for ruxolitinib cream 0.75% and 1.5%, respectively, and 5.7 for vehicle. Within about 12 hours of first application, mean itch NRS scores dropped –0.6 and –0.7 from baseline among those treated with ruxolitinib cream 0.75% and 1.5%, respectively, compared with –0.2 for those on the vehicle. At day 4, the decreases were –1.4 and –1.6 for ruxolitinib cream 0.75% and 1.5%, respectively, versus –0.6 for the vehicle (P = .026 and P = .005, respectively, vs. vehicle).
• At day 2, among the 187 patients with a baseline itch NRS score 4 or higher, more patients achieved 4-point or greater itch NRS improvement: 6.1% and 16.4% for ruxolitinib cream 0.75% and 1.5%, respectively versus 0% for vehicle. At day 7, the differences were 15.9% and 26.6% versus 3%, respectively. And by week 8, they increased to 30.1% and 43.2% versus 17.5% (P = .212 and P = .009), respectively.
• At week 2, 19% of patients in the 0.75% formulation group and 19.4% of patients in the 1.5% formulation group, compared with 5.3% in the vehicle group, reported no days of itch on question 1 of the Patient-Oriented Eczema Measure (POEM) questionnaire that evaluated various aspects of the disease over the previous week. By week 8, the differences grew to 34% and 30.8% versus 12.2%, respectively.
• Adverse events, reported by 14.4% and 22.1% of patients on 0.75% and 1.5% ruxolitinib, respectively, and by 32.8% of patients who received the vehicle, were headaches, upper respiratory tract infection, and application site pain.

Ruxolitinib may be an alternative to systemic immunosuppressives

Asked to comment on the results, Amy J. McMichael, MD, professor of dermatology at Wake Forest University School of Medicine, Winston-Salem, N.C., called itch “one of the major life disruptors in atopic dermatitis.”

Providers often assume that patients of different races respond similarly to treatment, but that is not always true, she noted in an email.

“This study proves ruxolitinib’s effectiveness in Black patients, who often have more severe atopic dermatitis signs and symptoms,” said Dr. McMichael, who was not involved in the study. “The fact that atopic dermatitis in patients of color has been singled out to examine efficacy is a great way to show that the findings are not just in those who have thinner plaques and potentially less longstanding thickening of the skin from scratching (lichenification),” she added.

Dr. McMichael welcomed the lack of systemic side effects and quick relief of itch with this treatment, noting that the effect on itch “is rare with other treatments and extremely rare with other topical medications.”

The effect of topical ruxolitinib on pruritus “was interesting and surprising because very few available topical medications can control itch,” she explained. “The strongest topical steroids can help with pruritus, but they have the risk for skin thinning (atrophy),” while topical ruxolitinib is not associated with skin atrophy.

“After topical steroids fail as first-line treatment, it is likely that more patients will be given this topical medication rather than be moved to immunosuppressive systemic medications,” she noted.

All study authors report relevant relationships with Incyte Corporation, which manufactures ruxolitinib and funded the study, and several authors report employment and shareholding interests in the company. Dr. McMichael reports no relevant relationship with the study.

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

A new study from the Centers for Disease Control and Prevention found that a surprising proportion of cases of carbapenem-resistant Enterobacterales (CRE) are found in isolates from patients in the community (CA-CRE). They had previously been thought to be health care–associated infections (HCA-CRE).

Traditionally, CRE has been thought of as a nosocomial infection, acquired in a hospital or other health care facility (nursing home, long-term acute care hospital, dialysis center, etc.). This is the first population-level study to show otherwise, with fully 10% of the CRE isolates found to be community acquired.

CREs are a group of multidrug-resistant bacteria considered an urgent health threat by the CDC because they can rapidly spread between patients, especially those who are most seriously ill and vulnerable, and because they are so difficult to treat. These patients often require treatment with toxic antibiotics, such as colistin, and carry a high mortality rate – up to 50% in some studies.

Overall, 30% of CREs carry a carbapenemase – an enzyme that can make them resistant to carbapenem antibiotics. The genes for this are readily transferable between bacteria and help account for their spread in hospitals.

But in this study, published in the American Journal of Infection Control, of the 12 isolates that underwent whole-genome sequencing, 42% of the CA-CRE isolates carried the carbapenemase gene. Lead author Sandra Bulens, MPH, a health scientist in the CDC’s division of health care quality promotion, said in an interview, “The findings highlight the potential for CP-CRE to move from health care settings into the community. The fact that 5 of the 12 isolates harbored a carbapenemase gene introduces new challenges for controlling spread of CP-CRE.”

CDC researchers analyzed data from eight U.S. metropolitan areas between 2012 and 2015 as part of the CDC’s Emerging Infections Program (EIP) health care–associated infections – community interface activity, which conducts surveillance for CRE and other drug-resistant gram-negative bacteria. Cases of CA-CRE were compared with HCA-CRE, with 1499 cases in 1,194 case-patients being analyzed. Though Klebsiella pneumoniae was the most common isolate, there were some differences between metropolitan areas.

The incidence of CRE cases per 100,000 population was 2.96 (95% confidence interval, 2.81-3.11) overall and 0.29 (95% CI, 0.25-0.25) for CA-CRE. Most CA-CRE cases were in White persons (73%) and women (84%). Urine cultures were the source of 98% of all CA-CRE cases, compared with 86% of HCA-CRE cases (P < .001). Though small numbers, the numbers of patients with CA-CRE without apparent underlying medical condition (n = 51; 37%) was greater when compared with patients with HCA-CRE (n = 36; 3%; P < .001).

Asked for independent comment, Lance Price, PhD, of George Washington University and the founding director of GW’s Antibiotic Resistance Action Center, Washington, said, “what’s striking about these data is that: ‘Who is the front line, at least in the United States for CRE?’ It’s women, older women. ... At some point, we have to frame drug resistance as a women’s health issue.”

Dr. Price noted that the 10% of patients with CA-CRE acquired it in the community. “I would argue that probably none of them had any idea, because there’s this silent community epidemic,” he said. “It’s asymptomatic carriage and transmission in the community. Somebody can be this walking reservoir of these really dangerous bacteria and have no idea.”

This is an increasingly serious problem for women, Dr. Price said, because, “with a community-acquired bladder infection, you’re going to call your doctor or go to an urgent care, and they’re not going to test you. They’re going to guess what you have, and they’re going to prescribe an antibiotic, and that antibiotic is going to fail. So then your bladder infection continues, and then you wait a few more days, and you start to get flank pain and kidney infection. ... If you start getting a fever, they might admit you. They are going to start treating you immediately, and they might miss it because you’ve got this organism that’s resistant to all the best antibiotics. ... The gateway to the blood is the UTI.”

Because of such empiric treatment and increasing resistance, the risk for treatment failure is quite high, especially for older women. Ms. Bulens, however, said that, “[although] 10% of CRE were in persons without health care risk factors, the proportion of all UTIs in this population that are CRE is going to be very, very small.”

This study involved cultures from 2012 to 2015. Before the pandemic, from 2012 to 2017, U.S. deaths from antibiotic resistance fell by 18% overall and by 30% in hospitals.

But in the first year of the COVID-19 pandemic, there was a 15% increase in infections and deaths from antibiotic-resistant (AMR), hospital-acquired bacteria. In 2020, 29,400 patients died from AMR infections. There was a 78% increase in carbapenem-resistant Acinetobacter baumannii health care–associated infections, a 35% increase in carbapenem-resistant Enterobacterales, and 32% increases in both multidrug-resistant Pseudomonas aeruginosa and extended-spectrum beta-lactamase–producing Enterobacterales. Aside from gram-negative bacteria, methicillin-resistant Staphylococcus aureus rose 13%, and Candida auris rose 60%. But owing to limited surveillance, recent sound figures are lacking.

Ms. Bulens and Dr. Price reported no relevant financial relationships.

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

A new study from the Centers for Disease Control and Prevention found that a surprising proportion of cases of carbapenem-resistant Enterobacterales (CRE) are found in isolates from patients in the community (CA-CRE). They had previously been thought to be health care–associated infections (HCA-CRE).

Traditionally, CRE has been thought of as a nosocomial infection, acquired in a hospital or other health care facility (nursing home, long-term acute care hospital, dialysis center, etc.). This is the first population-level study to show otherwise, with fully 10% of the CRE isolates found to be community acquired.

CREs are a group of multidrug-resistant bacteria considered an urgent health threat by the CDC because they can rapidly spread between patients, especially those who are most seriously ill and vulnerable, and because they are so difficult to treat. These patients often require treatment with toxic antibiotics, such as colistin, and carry a high mortality rate – up to 50% in some studies.

Overall, 30% of CREs carry a carbapenemase – an enzyme that can make them resistant to carbapenem antibiotics. The genes for this are readily transferable between bacteria and help account for their spread in hospitals.

But in this study, published in the American Journal of Infection Control, of the 12 isolates that underwent whole-genome sequencing, 42% of the CA-CRE isolates carried the carbapenemase gene. Lead author Sandra Bulens, MPH, a health scientist in the CDC’s division of health care quality promotion, said in an interview, “The findings highlight the potential for CP-CRE to move from health care settings into the community. The fact that 5 of the 12 isolates harbored a carbapenemase gene introduces new challenges for controlling spread of CP-CRE.”

CDC researchers analyzed data from eight U.S. metropolitan areas between 2012 and 2015 as part of the CDC’s Emerging Infections Program (EIP) health care–associated infections – community interface activity, which conducts surveillance for CRE and other drug-resistant gram-negative bacteria. Cases of CA-CRE were compared with HCA-CRE, with 1499 cases in 1,194 case-patients being analyzed. Though Klebsiella pneumoniae was the most common isolate, there were some differences between metropolitan areas.

The incidence of CRE cases per 100,000 population was 2.96 (95% confidence interval, 2.81-3.11) overall and 0.29 (95% CI, 0.25-0.25) for CA-CRE. Most CA-CRE cases were in White persons (73%) and women (84%). Urine cultures were the source of 98% of all CA-CRE cases, compared with 86% of HCA-CRE cases (P < .001). Though small numbers, the numbers of patients with CA-CRE without apparent underlying medical condition (n = 51; 37%) was greater when compared with patients with HCA-CRE (n = 36; 3%; P < .001).

Asked for independent comment, Lance Price, PhD, of George Washington University and the founding director of GW’s Antibiotic Resistance Action Center, Washington, said, “what’s striking about these data is that: ‘Who is the front line, at least in the United States for CRE?’ It’s women, older women. ... At some point, we have to frame drug resistance as a women’s health issue.”

Dr. Price noted that the 10% of patients with CA-CRE acquired it in the community. “I would argue that probably none of them had any idea, because there’s this silent community epidemic,” he said. “It’s asymptomatic carriage and transmission in the community. Somebody can be this walking reservoir of these really dangerous bacteria and have no idea.”

This is an increasingly serious problem for women, Dr. Price said, because, “with a community-acquired bladder infection, you’re going to call your doctor or go to an urgent care, and they’re not going to test you. They’re going to guess what you have, and they’re going to prescribe an antibiotic, and that antibiotic is going to fail. So then your bladder infection continues, and then you wait a few more days, and you start to get flank pain and kidney infection. ... If you start getting a fever, they might admit you. They are going to start treating you immediately, and they might miss it because you’ve got this organism that’s resistant to all the best antibiotics. ... The gateway to the blood is the UTI.”

Because of such empiric treatment and increasing resistance, the risk for treatment failure is quite high, especially for older women. Ms. Bulens, however, said that, “[although] 10% of CRE were in persons without health care risk factors, the proportion of all UTIs in this population that are CRE is going to be very, very small.”

This study involved cultures from 2012 to 2015. Before the pandemic, from 2012 to 2017, U.S. deaths from antibiotic resistance fell by 18% overall and by 30% in hospitals.

But in the first year of the COVID-19 pandemic, there was a 15% increase in infections and deaths from antibiotic-resistant (AMR), hospital-acquired bacteria. In 2020, 29,400 patients died from AMR infections. There was a 78% increase in carbapenem-resistant Acinetobacter baumannii health care–associated infections, a 35% increase in carbapenem-resistant Enterobacterales, and 32% increases in both multidrug-resistant Pseudomonas aeruginosa and extended-spectrum beta-lactamase–producing Enterobacterales. Aside from gram-negative bacteria, methicillin-resistant Staphylococcus aureus rose 13%, and Candida auris rose 60%. But owing to limited surveillance, recent sound figures are lacking.

Ms. Bulens and Dr. Price reported no relevant financial relationships.

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

A new study from the Centers for Disease Control and Prevention found that a surprising proportion of cases of carbapenem-resistant Enterobacterales (CRE) are found in isolates from patients in the community (CA-CRE). They had previously been thought to be health care–associated infections (HCA-CRE).

Traditionally, CRE has been thought of as a nosocomial infection, acquired in a hospital or other health care facility (nursing home, long-term acute care hospital, dialysis center, etc.). This is the first population-level study to show otherwise, with fully 10% of the CRE isolates found to be community acquired.

CREs are a group of multidrug-resistant bacteria considered an urgent health threat by the CDC because they can rapidly spread between patients, especially those who are most seriously ill and vulnerable, and because they are so difficult to treat. These patients often require treatment with toxic antibiotics, such as colistin, and carry a high mortality rate – up to 50% in some studies.

Overall, 30% of CREs carry a carbapenemase – an enzyme that can make them resistant to carbapenem antibiotics. The genes for this are readily transferable between bacteria and help account for their spread in hospitals.

But in this study, published in the American Journal of Infection Control, of the 12 isolates that underwent whole-genome sequencing, 42% of the CA-CRE isolates carried the carbapenemase gene. Lead author Sandra Bulens, MPH, a health scientist in the CDC’s division of health care quality promotion, said in an interview, “The findings highlight the potential for CP-CRE to move from health care settings into the community. The fact that 5 of the 12 isolates harbored a carbapenemase gene introduces new challenges for controlling spread of CP-CRE.”

CDC researchers analyzed data from eight U.S. metropolitan areas between 2012 and 2015 as part of the CDC’s Emerging Infections Program (EIP) health care–associated infections – community interface activity, which conducts surveillance for CRE and other drug-resistant gram-negative bacteria. Cases of CA-CRE were compared with HCA-CRE, with 1499 cases in 1,194 case-patients being analyzed. Though Klebsiella pneumoniae was the most common isolate, there were some differences between metropolitan areas.

The incidence of CRE cases per 100,000 population was 2.96 (95% confidence interval, 2.81-3.11) overall and 0.29 (95% CI, 0.25-0.25) for CA-CRE. Most CA-CRE cases were in White persons (73%) and women (84%). Urine cultures were the source of 98% of all CA-CRE cases, compared with 86% of HCA-CRE cases (P < .001). Though small numbers, the numbers of patients with CA-CRE without apparent underlying medical condition (n = 51; 37%) was greater when compared with patients with HCA-CRE (n = 36; 3%; P < .001).

Asked for independent comment, Lance Price, PhD, of George Washington University and the founding director of GW’s Antibiotic Resistance Action Center, Washington, said, “what’s striking about these data is that: ‘Who is the front line, at least in the United States for CRE?’ It’s women, older women. ... At some point, we have to frame drug resistance as a women’s health issue.”

Dr. Price noted that the 10% of patients with CA-CRE acquired it in the community. “I would argue that probably none of them had any idea, because there’s this silent community epidemic,” he said. “It’s asymptomatic carriage and transmission in the community. Somebody can be this walking reservoir of these really dangerous bacteria and have no idea.”

This is an increasingly serious problem for women, Dr. Price said, because, “with a community-acquired bladder infection, you’re going to call your doctor or go to an urgent care, and they’re not going to test you. They’re going to guess what you have, and they’re going to prescribe an antibiotic, and that antibiotic is going to fail. So then your bladder infection continues, and then you wait a few more days, and you start to get flank pain and kidney infection. ... If you start getting a fever, they might admit you. They are going to start treating you immediately, and they might miss it because you’ve got this organism that’s resistant to all the best antibiotics. ... The gateway to the blood is the UTI.”

Because of such empiric treatment and increasing resistance, the risk for treatment failure is quite high, especially for older women. Ms. Bulens, however, said that, “[although] 10% of CRE were in persons without health care risk factors, the proportion of all UTIs in this population that are CRE is going to be very, very small.”

This study involved cultures from 2012 to 2015. Before the pandemic, from 2012 to 2017, U.S. deaths from antibiotic resistance fell by 18% overall and by 30% in hospitals.

But in the first year of the COVID-19 pandemic, there was a 15% increase in infections and deaths from antibiotic-resistant (AMR), hospital-acquired bacteria. In 2020, 29,400 patients died from AMR infections. There was a 78% increase in carbapenem-resistant Acinetobacter baumannii health care–associated infections, a 35% increase in carbapenem-resistant Enterobacterales, and 32% increases in both multidrug-resistant Pseudomonas aeruginosa and extended-spectrum beta-lactamase–producing Enterobacterales. Aside from gram-negative bacteria, methicillin-resistant Staphylococcus aureus rose 13%, and Candida auris rose 60%. But owing to limited surveillance, recent sound figures are lacking.

Ms. Bulens and Dr. Price reported no relevant financial relationships.

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

The combination of a tyrosine kinase inhibitor with an immune checkpoint inhibitor significantly improved progression-free survival in patients with hepatocellular carcinoma, shows a new study.

While the combination has been shown to be beneficial in renal cell carcinoma and other solid tumor types, it has never before been tested in a phase 3 clinical trial for hepatocellular carcinoma until now.

The new study, published in The Lancet Oncology, included 837 patients from 178 hospital in 32 countries who were enrolled in the study (called COSMIC-312) between December 2018 and August 2020. 432 patients were randomly assigned to receive a combination of cabozantinib (Cabometyx, Exelixis), a tyrosine kinase inhibitor (TKI), and atezolizumab (Tecentriq, Genentech), a PD-L1 inhibitor. While 217 patients were treated with sorafenib (Nexavar, Bayer) alone and 188 patients were treated with cabozantinib.

Clinically meaningful improvements in progression-free survival, increased disease control and lower primary progression were seen in patients who received the cabozantinib and atezolizumab combination therapy over patients who were treated with sorafenib. However, there was no improvement in overall survival.

“The improvement in progression-free survival with cabozantinib plus atezolizumab in this study shows that the combination confers clinical benefit for patients with advanced hepatocellular carcinoma previously untreated with systemic anticancer therapy,” wrote the authors of the study, led by Robin Kate Kelley, MD, a gastrointestinal oncologist with the University of California, San Francisco, and Lorenza Rimassa, MD, a gastrointestinal oncologist with Humanitas University, Milan. “The absence of a benefit in overall survival, along with the availability of atezolizumab in combination with bevacizumab, indicates the need for additional studies to determine if cabozantinib plus atezolizumab would be an appropriate first-line treatment option in select patient populations.”

For symptomatic patients with high disease burden or main portal vein occlusion who are at risk for impending complications, controlling the disease as quickly as possible is vital, the authors wrote. “Underlying chronic liver disease is nearly universal in patients with hepatocellular carcinoma and the risk of gastrointestinal bleeding is high in this population, particularly if portal vein tumor thrombus is present.”

Hepatocellular carcinoma (HCC) is an angiogenic tumor, making it a logical target for TKIs that target vascular endothelial growth factor. The TKI sorafenib was the first to be approved as a first-line treatment for HCC, and since then immune checkpoint inhibitors have been shown to induce durable responses in the first-line setting, but have not improved overall survival in randomized trials.
 

Study methodology

In the study, after a median follow-up of 15.8 months, median progression-free survival was 6.8 months in the combination group and 4.2 months in the sorafenib group (hazard ratio, 0.63; P = .0012). The median overall survival was 15.4 months in the combination group and 15.5 months in the sorafenib group (not significant). Grade 3-4 adverse events included an increase in ALT, which occurred in 9% of the combination group, 3% of the sorafenib group, and 6% of the cabozantinib only group; hypertension (9%, 8%, and 12%, respectively); an increase in AST increase (9%, 4%, 10%); and palmar-plantar erythrodysesthesia (8%, 8%, 9%). Serious treatment-related adverse events occurred in 18% of patients in the combination arm, 8% in the sorafenib arm, and 13% in the cabozantinib arm.

There were no excess serious bleeding events in the treatment groups containing cabozantinib, compared with sorafenib which is noteworthy because HCC patients are at high risk for gastrointestinal bleeding.

Treatment-related grade 5 events were rare, occurring in 1% (six patients) of the combination group, and in just one patient in both the sorafenib and cabozantinib groups.

Although the results suggest promising clinical benefit, the lack of overall survival benefit limit the implications of these findings. Since atezolizumab combined with bevacizumab is also available for this patient population, more research is needed to determine if cabozantinib plus atezolizumab can become a first-line option.

The study had some limitations: Participants had to have a Child-Pugh class of A, though there was no requirement to assess for fibrosis or cirrhosis. Otherwise there were few barriers to study entry.

The study was sponsored by Exelixis (Alameda) and Ipsen (Boulogne-Billancourt, France).

The combination of a tyrosine kinase inhibitor with an immune checkpoint inhibitor significantly improved progression-free survival in patients with hepatocellular carcinoma, shows a new study.

While the combination has been shown to be beneficial in renal cell carcinoma and other solid tumor types, it has never before been tested in a phase 3 clinical trial for hepatocellular carcinoma until now.

The new study, published in The Lancet Oncology, included 837 patients from 178 hospital in 32 countries who were enrolled in the study (called COSMIC-312) between December 2018 and August 2020. 432 patients were randomly assigned to receive a combination of cabozantinib (Cabometyx, Exelixis), a tyrosine kinase inhibitor (TKI), and atezolizumab (Tecentriq, Genentech), a PD-L1 inhibitor. While 217 patients were treated with sorafenib (Nexavar, Bayer) alone and 188 patients were treated with cabozantinib.

Clinically meaningful improvements in progression-free survival, increased disease control and lower primary progression were seen in patients who received the cabozantinib and atezolizumab combination therapy over patients who were treated with sorafenib. However, there was no improvement in overall survival.

“The improvement in progression-free survival with cabozantinib plus atezolizumab in this study shows that the combination confers clinical benefit for patients with advanced hepatocellular carcinoma previously untreated with systemic anticancer therapy,” wrote the authors of the study, led by Robin Kate Kelley, MD, a gastrointestinal oncologist with the University of California, San Francisco, and Lorenza Rimassa, MD, a gastrointestinal oncologist with Humanitas University, Milan. “The absence of a benefit in overall survival, along with the availability of atezolizumab in combination with bevacizumab, indicates the need for additional studies to determine if cabozantinib plus atezolizumab would be an appropriate first-line treatment option in select patient populations.”

For symptomatic patients with high disease burden or main portal vein occlusion who are at risk for impending complications, controlling the disease as quickly as possible is vital, the authors wrote. “Underlying chronic liver disease is nearly universal in patients with hepatocellular carcinoma and the risk of gastrointestinal bleeding is high in this population, particularly if portal vein tumor thrombus is present.”

Hepatocellular carcinoma (HCC) is an angiogenic tumor, making it a logical target for TKIs that target vascular endothelial growth factor. The TKI sorafenib was the first to be approved as a first-line treatment for HCC, and since then immune checkpoint inhibitors have been shown to induce durable responses in the first-line setting, but have not improved overall survival in randomized trials.
 

Study methodology

In the study, after a median follow-up of 15.8 months, median progression-free survival was 6.8 months in the combination group and 4.2 months in the sorafenib group (hazard ratio, 0.63; P = .0012). The median overall survival was 15.4 months in the combination group and 15.5 months in the sorafenib group (not significant). Grade 3-4 adverse events included an increase in ALT, which occurred in 9% of the combination group, 3% of the sorafenib group, and 6% of the cabozantinib only group; hypertension (9%, 8%, and 12%, respectively); an increase in AST increase (9%, 4%, 10%); and palmar-plantar erythrodysesthesia (8%, 8%, 9%). Serious treatment-related adverse events occurred in 18% of patients in the combination arm, 8% in the sorafenib arm, and 13% in the cabozantinib arm.

There were no excess serious bleeding events in the treatment groups containing cabozantinib, compared with sorafenib which is noteworthy because HCC patients are at high risk for gastrointestinal bleeding.

Treatment-related grade 5 events were rare, occurring in 1% (six patients) of the combination group, and in just one patient in both the sorafenib and cabozantinib groups.

Although the results suggest promising clinical benefit, the lack of overall survival benefit limit the implications of these findings. Since atezolizumab combined with bevacizumab is also available for this patient population, more research is needed to determine if cabozantinib plus atezolizumab can become a first-line option.

The study had some limitations: Participants had to have a Child-Pugh class of A, though there was no requirement to assess for fibrosis or cirrhosis. Otherwise there were few barriers to study entry.

The study was sponsored by Exelixis (Alameda) and Ipsen (Boulogne-Billancourt, France).

The combination of a tyrosine kinase inhibitor with an immune checkpoint inhibitor significantly improved progression-free survival in patients with hepatocellular carcinoma, shows a new study.

While the combination has been shown to be beneficial in renal cell carcinoma and other solid tumor types, it has never before been tested in a phase 3 clinical trial for hepatocellular carcinoma until now.

The new study, published in The Lancet Oncology, included 837 patients from 178 hospital in 32 countries who were enrolled in the study (called COSMIC-312) between December 2018 and August 2020. 432 patients were randomly assigned to receive a combination of cabozantinib (Cabometyx, Exelixis), a tyrosine kinase inhibitor (TKI), and atezolizumab (Tecentriq, Genentech), a PD-L1 inhibitor. While 217 patients were treated with sorafenib (Nexavar, Bayer) alone and 188 patients were treated with cabozantinib.

Clinically meaningful improvements in progression-free survival, increased disease control and lower primary progression were seen in patients who received the cabozantinib and atezolizumab combination therapy over patients who were treated with sorafenib. However, there was no improvement in overall survival.

“The improvement in progression-free survival with cabozantinib plus atezolizumab in this study shows that the combination confers clinical benefit for patients with advanced hepatocellular carcinoma previously untreated with systemic anticancer therapy,” wrote the authors of the study, led by Robin Kate Kelley, MD, a gastrointestinal oncologist with the University of California, San Francisco, and Lorenza Rimassa, MD, a gastrointestinal oncologist with Humanitas University, Milan. “The absence of a benefit in overall survival, along with the availability of atezolizumab in combination with bevacizumab, indicates the need for additional studies to determine if cabozantinib plus atezolizumab would be an appropriate first-line treatment option in select patient populations.”

For symptomatic patients with high disease burden or main portal vein occlusion who are at risk for impending complications, controlling the disease as quickly as possible is vital, the authors wrote. “Underlying chronic liver disease is nearly universal in patients with hepatocellular carcinoma and the risk of gastrointestinal bleeding is high in this population, particularly if portal vein tumor thrombus is present.”

Hepatocellular carcinoma (HCC) is an angiogenic tumor, making it a logical target for TKIs that target vascular endothelial growth factor. The TKI sorafenib was the first to be approved as a first-line treatment for HCC, and since then immune checkpoint inhibitors have been shown to induce durable responses in the first-line setting, but have not improved overall survival in randomized trials.
 

Study methodology

In the study, after a median follow-up of 15.8 months, median progression-free survival was 6.8 months in the combination group and 4.2 months in the sorafenib group (hazard ratio, 0.63; P = .0012). The median overall survival was 15.4 months in the combination group and 15.5 months in the sorafenib group (not significant). Grade 3-4 adverse events included an increase in ALT, which occurred in 9% of the combination group, 3% of the sorafenib group, and 6% of the cabozantinib only group; hypertension (9%, 8%, and 12%, respectively); an increase in AST increase (9%, 4%, 10%); and palmar-plantar erythrodysesthesia (8%, 8%, 9%). Serious treatment-related adverse events occurred in 18% of patients in the combination arm, 8% in the sorafenib arm, and 13% in the cabozantinib arm.

There were no excess serious bleeding events in the treatment groups containing cabozantinib, compared with sorafenib which is noteworthy because HCC patients are at high risk for gastrointestinal bleeding.

Treatment-related grade 5 events were rare, occurring in 1% (six patients) of the combination group, and in just one patient in both the sorafenib and cabozantinib groups.

Although the results suggest promising clinical benefit, the lack of overall survival benefit limit the implications of these findings. Since atezolizumab combined with bevacizumab is also available for this patient population, more research is needed to determine if cabozantinib plus atezolizumab can become a first-line option.

The study had some limitations: Participants had to have a Child-Pugh class of A, though there was no requirement to assess for fibrosis or cirrhosis. Otherwise there were few barriers to study entry.

The study was sponsored by Exelixis (Alameda) and Ipsen (Boulogne-Billancourt, France).

MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.

While both regimens showed similar efficacy for HIV control, the B/F/TAF regimen produced better HBV results, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.

The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.

For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).

No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.

“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”

“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question. 

“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.

The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.

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

MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.

While both regimens showed similar efficacy for HIV control, the B/F/TAF regimen produced better HBV results, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.

The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.

For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).

No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.

“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”

“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question. 

“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.

The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.

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

MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.

While both regimens showed similar efficacy for HIV control, the B/F/TAF regimen produced better HBV results, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.

The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.

For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).

No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.

“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”

“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question. 

“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.

The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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