Kate Johnson

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

Treatment with Janus kinase (JAK) inhibitors does not appear to be associated with an increased risk of venous thromboembolism (VTE) in patients with atopic dermatitis (AD), according to a new systemic review and meta-analysis, published online in JAMA Dermatology.

“These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD,” Tai-Li Chen, MD, of Taipei (Taiwan) Veterans General Hospital, Taipei, and colleagues wrote in the study.

The results shed some welcome light on treatment for this dermatologic population, for whom enthusiasm about JAK inhibitors was dampened by the addition of a boxed warning to the labels of JAK inhibitors last year, required by the Food and Drug Administration. The warning, which describes an increased risk of “serious heart-related events such as heart attack or stroke, cancer, blood clots, and death” was triggered by results of the ORAL Surveillance study of patients with rheumatoid arthritis (RA) treated with tofacitinib.

The boxed warning is also included in the labels of topical ruxolitinib, a JAK inhibitor approved by the FDA for mild to moderate AD in 2021, and in the labels of two oral JAK inhibitors, upadacitinib and abrocitinib, approved by the FDA for treating moderate to severe AD in January 2022.

Despite the new findings, some dermatologists are still urging caution.

“All the JAK inhibitor trials are short term. I still think the precautionary principle applies and we need to counsel on the risks of JAKs,” tweeted Aaron Drucker, MD, a dermatologist at Women’s College Hospital, and associate professor at the University of Toronto. “It is great to have these as options for our patients. But we need to be aware of the risks associated with this class of medications, counsel patients about them when we are informing them of the risks and benefits of treatment options, and wait for more data specific to this population to make even more informed decisions,” he told this news organization.

The meta-analysis examined both the risk of incident VTE in untreated patients with AD compared with non-AD patients, as well as the risk of VTE in AD patients treated with JAK inhibitors compared with those on either placebo or dupilumab. Four JAK inhibitors were studied: abrocitinib, baricitinib (under FDA review for AD), upadacitinib, and SHR0302 (in clinical trials).

Two studies (458,206 participants) found the overall incidence rate of VTE for patients with AD was 0.23 events per 100 patient-years. The risk was did not differ from that in non-AD patients (pooled hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.62-1.45).

Another 15 studies included 8,787 participants with AD and found no significant differences in the rates of VTE in AD patients treated with JAK inhibitors (0.05%) versus those treated with placebo or dupilumab (0.03%). However “with the increasing applications of JAK inhibitors in AD, more clinical data are needed to identify patients at high risk for VTE,” noted the authors.

“We need more, long-term data,” agreed Dr. Drucker, adding that a major issue is the short-term nature of AD trials to date (generally up to 16 weeks), which “don’t provide adequate reassurance.” He said although the FDA’s boxed warning was prompted by a trial in RA patients treated with tofacitinib (a less selective JAK inhibitor than those approved by the FDA for AD), and the same risks have not been demonstrated specifically for the JAK inhibitors used for a patients with AD, he still remains cautious.

While agreeing on the need for more long-term data, Andrew Blauvelt, MD, MBA, president of Oregon Medical Research Center, Portland, said that the new findings should “provide reassurance” to dermatologists and are “consonant with recent published meta-analyses reporting no increased VTE risk in patients with psoriasis, RA, or inflammatory bowel disease treated with JAK inhibitors” in Arthritis & Rheumatology, and Mayo Clinic Proceedings.

In an interview, Dr. Blauvelt said that safety profiles emerging for the newer JAK inhibitors, which block JAK 1/2, have been overshadowed by the older RA data for tofacitinib – which is a JAK 1/3 inhibitor, “despite emerging long-term, monotherapy, clinical study data for dermatologic diseases showing no or rare risks of developing severe adverse events outlined in the boxed warnings.”

Both Dr. Blauvelt and Dr. Drucker pointed out that people with RA tend to have more comorbidities than those with AD that would predispose them to adverse events. In fact, “approximately 75% of patients in the ORAL Surveillance study were also on concomitant methotrexate and/or prednisone, which can greatly confound safety results,” said Dr. Blauvelt.

The study authors did not report any disclosures. No funding source for the study was provided. Dr. Drucker has no relevant disclosures. Dr. Blauvelt has been a clinical study investigator in trials for AD treatments, including JAK inhibitors; his disclosures include serving as a speaker, scientific adviser, and/or clinical study investigator for multiple companies including AbbVie, Arcutis, Bristol-Myers Squibb, Pfizer, Incyte, Regeneron, Sanofi Genzyme, and UCB Pharma.

Six years ago, Kim Bowles had a double mastectomy after being diagnosed with stage 3 breast cancer. Instead of opting for reconstruction, she decided to go “flat.” At 35, she had already breast fed both of her children, and didn’t want breasts anymore.

She asked her surgeon for an aesthetic flat closure, showing him photos of a smooth chest with no excess skin flaps. Although he agreed to her request in the office, he reneged in the operating room.

As the anesthesia took effect he said, “I’ll just leave a little extra skin, in case you change your mind.”

The last thing she remembers is telling him “no.”

When Ms. Bowles woke up, she saw excess tissue instead of the smooth chest she had requested. When she was eventually well enough, she staged a topless sit-in at the hospital and marched outside with a placard, baring her breastless, disfigured chest.

“Do I need a B-cup side-boob?” she asked, pulling at her lateral excess tissue, often referred to as dog ears. “You would never think that a surgeon would leave somebody looking like that,” she said in an interview.

Based on her experience, Ms. Bowles coined the term “flat denial” to describe what her surgeon did.
 

The weight of flat denial

In a recent study, Deanna Attai, MD, a breast surgeon at University of California, Los Angeles, discovered that more than one in five women who want a flat closure experience flat denial.

But well before that survey, Dr. Attai first came across flat denial more than a decade ago when a patient came to her for a second opinion after another surgeon insisted the patient see a psychiatrist when she requested a flat closure. Dr. Attai performed the flat closure for her instead.

But Dr. Attai said flat denial can take many forms. Some experiences may closely match the paternalistic encounter Ms. Bowles had, where a surgeon disregards a patient’s request. Other surgeons may simply be ignorant that a flat closure can be achieved aesthetically or that patients would even want this option.

This resistance aligns with Hester Schnipper’s experience as an oncology social worker. In her 45-year career, she has often found herself pushing back against breast surgeons who present reconstruction as if it were the only option for patients after mastectomy.

“And because most women are so overwhelmed, so scared, so stressed, they tend to go with whatever the doctor suggests,” said Ms. Schnipper.

Whatever form flat denial takes, the outcome can be damaging to the patient.

“This isn’t just ‘my scar’s a little thick.’ This is much more,” Dr. Attai said. “How do you even put a prosthesis on that? And if you’re not going to do a prosthesis in a bra, how do you even wear a shirt with all of that? It becomes a cleaning issue and depending on how things scar down you can get irregular fibrosis.”

What’s more, the harms of flat denial can extend beyond the physical scars.

Like Ms. Bowles, Anne Marie Champagne had made her desire for a flat closure clear to her surgeon before undergoing a mastectomy in 2009. The surgeon also reneged in the operating room while Champagne was unconscious and unable to object.

Ms. Champagne told The Washington Post that her surgeon’s justification for his actions left her feeling “profound grief, a combination of heartache and anger.

“I couldn’t believe that my surgeon would make a decision for me while I was under anesthesia that went against everything we had discussed – what I had consented to.”

Although it’s not clear how often women experience flat denial, discussions surrounding the issue have increased in recent years.

Ms. Bowles started a patient advocacy organization called “Not Putting on A Shirt” to help other women. And Dr. Attai moderates a Twitter group, called #BCSM or Breast Cancer Social Media, where patients share their experiences of breast cancer treatment, including in some cases flat denial.

“In getting to know so many women in the online space, an early observation was that the conversations online were different than what we had in the office,” Dr. Attai said. Online, “women were less guarded and more open about sharing the entirety of their breast cancer experience, including the more painful and raw moments.”

Being immersed in these moments, it also became clear to Dr. Attai that members of the treatment team don’t always recognize what is most important to a patient. “We might not ask, we might not allow them the time to express their preferences, or we might not really hear them,” she said.
 

An evolving awareness

National figures on the prevalence of flat closures remain elusive, but it has always been an option. And data indicate that many women choose no reconstruction after mastectomy.

One U.S. survey of women undergoing mastectomy between 2005 and 2007 found that 58% opted not to receive reconstruction, and a more recent British National Mastectomy and Breast Reconstruction Audit from 2011 found 70% chose no reconstruction.

“I definitely have seen more patients requesting to go flat after mastectomy, likely as they feel more empowered to make this decision,” Roshni Rao, MD, chief of breast surgery at Columbia University Medical Center, New York, told The Washington Post.

But to better understand the scope of flat denial, Dr. Attai and colleagues conducted a survey, published in Annals of Surgical Oncology. In it, she found that, among 931 women who had opted to go flat after mastectomy, 22% had experienced flat denial. That meant not being offered the option of going flat, not being supported in their choice to go flat, or not receiving the flat closure surgery initially agreed upon.

In the spring of 2022, Dr. Attai, past president of the American Society of Breast Surgeons, took her results to the society’s annual meeting. The goal was to bring to light aesthetic flat closure techniques as well as the harms of flat denial, presenting photos of the sagging, shriveled skin flaps alongside her analysis.

“No one ever goes into an operation intending it to look like those horrible pictures,” she said.

Asking for “no breast mound reconstruction” should imply a nice neat flat closure, or an aesthetic flat closure, Dr. Attai explained. “A patient should not have to specify she wants the surgeon to make all efforts to remove redundant and excess skin and fat, but I do think having the discussion and making preferences very clear is important, especially as we’ve seen that some patients are not getting the desired outcome.”

To help improve education and communication, the board of “No Putting on a Shirt” also had an exhibitor’s booth focused on aesthetic flat closures at the ASBrS meeting.

And given this growing awareness, the National Accreditation Program for Breast Centers has begun asking breast centers to report their process for shared decision-making on postmastectomy choices and provide proof that patients’ closure choices are being heard and followed.
 

A shift toward aesthetics

Despite a growing interest in flat closure aesthetics, the landscape shift is still relatively new.

The traditional mastectomy training Dr. Attai and colleagues went through in the 1990s did not emphasize aesthetics.

“I just removed the breast and then I left the room,” she said, explaining that the plastic surgeon took charge of the reconstruction. “We never really learned how to make a nice, neat closure.”

Abhishek Chatterjee, MD, MBA, a breast surgical oncologist and board-certified plastic surgeon, agreed that aesthetics have become more central in the field.

“A decade ago, I would argue that ... it wasn’t in the training program,” but today breast surgery fellowships now include “flat closures that are aesthetically appropriate,” said Dr. Chatterjee, who works at Tufts Medical Center in Boston and is vice chair of the ASBrS oncoplastics committee.

“In my mind, and in any surgeon’s mind, when you do something, you have to do it well ... and with that, aesthetics should be presumed,” he added.

But the term “aesthetic flat closure” was only adopted by the National Cancer Institute in 2020. The NCI, which considers an aesthetic flat closure reconstructive not cosmetic surgery, defines it as rebuilding the shape of the chest wall after breasts are removed, and involves contouring and eliminating excess tissue to create a smooth, flat chest wall.

Achieving this smooth look requires a skilled surgeon trained in flat closure reconstruction, which is not necessarily a guarantee. To help women find a surgeon, “Not Putting on A Shirt” has a flat friendly directory where patients can recommend surgeons who provide aesthetic flat closures. As of August 2022, the list has now grown to over 300 surgeons.

Dr. Chatterjee said the ASBrS is actively involved in training surgeons in aesthetic flat closure. Given this shift, he said most general or breast surgeons should have the skill set to design mastectomy flaps that enable a flat closure with no excess skin, but there are some caveats.

For instance, he noted, if a woman has a lot of breast tissue and excess skin in the outer, lateral folds of the axilla, “it is very, very hard to get a flat closure” and in those rare circumstances, a breast surgeon may need assistance from a plastic surgeon.

But Dr. Attai found a significant gap still exists between what should be done and what is being done in practice.

Part of that disconnect may stem from the lack of a standard of care.

In a recent publication, a team of plastic surgeons from New York University noted that, to date, “there is no plastic surgery literature on specific techniques to achieve an aesthetic flat closure after mastectomy.”

And Dr. Attai added, “there is really no way to know at this point what women are getting when they choose no breast mound reconstruction.”

Physicians may also simply not understand what their patients want.

Dr. Attai said she was “blown away” by the reaction to her presentation on flat denial at ASBrS in April. “I had a lot of members come up to me afterwards and say ‘I had no idea that patients would want this. I am guilty of not offering this.’ ”

In addition, Dr. Chatterjee said, patients may now have “much higher” expectations for a smooth, symmetrical look “versus an outcome with excess skin and bumps.”

But Ms. Bowles said the desire for a more aesthetically pleasing look is nothing new.

“Women have always cared about how they look, they are just shamed into accepting a lesser result,” she argued. “If you look at why women go flat, the primary reason is they don’t want more surgery, not ‘I don’t care what I look like.’ ”

Three years after the mastectomy that left flaps of skin hanging from her chest, Ms. Bowles finally had a revision surgery to achieve the flat closure aesthetic she had wanted from the get-go.

“Nobody expects perfection, but I think the important thing is to have a standard of care that’s optimal,” said Ms. Bowles. “A patient like me should not have needed another surgery.”

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

Six years ago, Kim Bowles had a double mastectomy after being diagnosed with stage 3 breast cancer. Instead of opting for reconstruction, she decided to go “flat.” At 35, she had already breast fed both of her children, and didn’t want breasts anymore.

She asked her surgeon for an aesthetic flat closure, showing him photos of a smooth chest with no excess skin flaps. Although he agreed to her request in the office, he reneged in the operating room.

As the anesthesia took effect he said, “I’ll just leave a little extra skin, in case you change your mind.”

The last thing she remembers is telling him “no.”

When Ms. Bowles woke up, she saw excess tissue instead of the smooth chest she had requested. When she was eventually well enough, she staged a topless sit-in at the hospital and marched outside with a placard, baring her breastless, disfigured chest.

“Do I need a B-cup side-boob?” she asked, pulling at her lateral excess tissue, often referred to as dog ears. “You would never think that a surgeon would leave somebody looking like that,” she said in an interview.

Based on her experience, Ms. Bowles coined the term “flat denial” to describe what her surgeon did.
 

The weight of flat denial

In a recent study, Deanna Attai, MD, a breast surgeon at University of California, Los Angeles, discovered that more than one in five women who want a flat closure experience flat denial.

But well before that survey, Dr. Attai first came across flat denial more than a decade ago when a patient came to her for a second opinion after another surgeon insisted the patient see a psychiatrist when she requested a flat closure. Dr. Attai performed the flat closure for her instead.

But Dr. Attai said flat denial can take many forms. Some experiences may closely match the paternalistic encounter Ms. Bowles had, where a surgeon disregards a patient’s request. Other surgeons may simply be ignorant that a flat closure can be achieved aesthetically or that patients would even want this option.

This resistance aligns with Hester Schnipper’s experience as an oncology social worker. In her 45-year career, she has often found herself pushing back against breast surgeons who present reconstruction as if it were the only option for patients after mastectomy.

“And because most women are so overwhelmed, so scared, so stressed, they tend to go with whatever the doctor suggests,” said Ms. Schnipper.

Whatever form flat denial takes, the outcome can be damaging to the patient.

“This isn’t just ‘my scar’s a little thick.’ This is much more,” Dr. Attai said. “How do you even put a prosthesis on that? And if you’re not going to do a prosthesis in a bra, how do you even wear a shirt with all of that? It becomes a cleaning issue and depending on how things scar down you can get irregular fibrosis.”

What’s more, the harms of flat denial can extend beyond the physical scars.

Like Ms. Bowles, Anne Marie Champagne had made her desire for a flat closure clear to her surgeon before undergoing a mastectomy in 2009. The surgeon also reneged in the operating room while Champagne was unconscious and unable to object.

Ms. Champagne told The Washington Post that her surgeon’s justification for his actions left her feeling “profound grief, a combination of heartache and anger.

“I couldn’t believe that my surgeon would make a decision for me while I was under anesthesia that went against everything we had discussed – what I had consented to.”

Although it’s not clear how often women experience flat denial, discussions surrounding the issue have increased in recent years.

Ms. Bowles started a patient advocacy organization called “Not Putting on A Shirt” to help other women. And Dr. Attai moderates a Twitter group, called #BCSM or Breast Cancer Social Media, where patients share their experiences of breast cancer treatment, including in some cases flat denial.

“In getting to know so many women in the online space, an early observation was that the conversations online were different than what we had in the office,” Dr. Attai said. Online, “women were less guarded and more open about sharing the entirety of their breast cancer experience, including the more painful and raw moments.”

Being immersed in these moments, it also became clear to Dr. Attai that members of the treatment team don’t always recognize what is most important to a patient. “We might not ask, we might not allow them the time to express their preferences, or we might not really hear them,” she said.
 

An evolving awareness

National figures on the prevalence of flat closures remain elusive, but it has always been an option. And data indicate that many women choose no reconstruction after mastectomy.

One U.S. survey of women undergoing mastectomy between 2005 and 2007 found that 58% opted not to receive reconstruction, and a more recent British National Mastectomy and Breast Reconstruction Audit from 2011 found 70% chose no reconstruction.

“I definitely have seen more patients requesting to go flat after mastectomy, likely as they feel more empowered to make this decision,” Roshni Rao, MD, chief of breast surgery at Columbia University Medical Center, New York, told The Washington Post.

But to better understand the scope of flat denial, Dr. Attai and colleagues conducted a survey, published in Annals of Surgical Oncology. In it, she found that, among 931 women who had opted to go flat after mastectomy, 22% had experienced flat denial. That meant not being offered the option of going flat, not being supported in their choice to go flat, or not receiving the flat closure surgery initially agreed upon.

In the spring of 2022, Dr. Attai, past president of the American Society of Breast Surgeons, took her results to the society’s annual meeting. The goal was to bring to light aesthetic flat closure techniques as well as the harms of flat denial, presenting photos of the sagging, shriveled skin flaps alongside her analysis.

“No one ever goes into an operation intending it to look like those horrible pictures,” she said.

Asking for “no breast mound reconstruction” should imply a nice neat flat closure, or an aesthetic flat closure, Dr. Attai explained. “A patient should not have to specify she wants the surgeon to make all efforts to remove redundant and excess skin and fat, but I do think having the discussion and making preferences very clear is important, especially as we’ve seen that some patients are not getting the desired outcome.”

To help improve education and communication, the board of “No Putting on a Shirt” also had an exhibitor’s booth focused on aesthetic flat closures at the ASBrS meeting.

And given this growing awareness, the National Accreditation Program for Breast Centers has begun asking breast centers to report their process for shared decision-making on postmastectomy choices and provide proof that patients’ closure choices are being heard and followed.
 

A shift toward aesthetics

Despite a growing interest in flat closure aesthetics, the landscape shift is still relatively new.

The traditional mastectomy training Dr. Attai and colleagues went through in the 1990s did not emphasize aesthetics.

“I just removed the breast and then I left the room,” she said, explaining that the plastic surgeon took charge of the reconstruction. “We never really learned how to make a nice, neat closure.”

Abhishek Chatterjee, MD, MBA, a breast surgical oncologist and board-certified plastic surgeon, agreed that aesthetics have become more central in the field.

“A decade ago, I would argue that ... it wasn’t in the training program,” but today breast surgery fellowships now include “flat closures that are aesthetically appropriate,” said Dr. Chatterjee, who works at Tufts Medical Center in Boston and is vice chair of the ASBrS oncoplastics committee.

“In my mind, and in any surgeon’s mind, when you do something, you have to do it well ... and with that, aesthetics should be presumed,” he added.

But the term “aesthetic flat closure” was only adopted by the National Cancer Institute in 2020. The NCI, which considers an aesthetic flat closure reconstructive not cosmetic surgery, defines it as rebuilding the shape of the chest wall after breasts are removed, and involves contouring and eliminating excess tissue to create a smooth, flat chest wall.

Achieving this smooth look requires a skilled surgeon trained in flat closure reconstruction, which is not necessarily a guarantee. To help women find a surgeon, “Not Putting on A Shirt” has a flat friendly directory where patients can recommend surgeons who provide aesthetic flat closures. As of August 2022, the list has now grown to over 300 surgeons.

Dr. Chatterjee said the ASBrS is actively involved in training surgeons in aesthetic flat closure. Given this shift, he said most general or breast surgeons should have the skill set to design mastectomy flaps that enable a flat closure with no excess skin, but there are some caveats.

For instance, he noted, if a woman has a lot of breast tissue and excess skin in the outer, lateral folds of the axilla, “it is very, very hard to get a flat closure” and in those rare circumstances, a breast surgeon may need assistance from a plastic surgeon.

But Dr. Attai found a significant gap still exists between what should be done and what is being done in practice.

Part of that disconnect may stem from the lack of a standard of care.

In a recent publication, a team of plastic surgeons from New York University noted that, to date, “there is no plastic surgery literature on specific techniques to achieve an aesthetic flat closure after mastectomy.”

And Dr. Attai added, “there is really no way to know at this point what women are getting when they choose no breast mound reconstruction.”

Physicians may also simply not understand what their patients want.

Dr. Attai said she was “blown away” by the reaction to her presentation on flat denial at ASBrS in April. “I had a lot of members come up to me afterwards and say ‘I had no idea that patients would want this. I am guilty of not offering this.’ ”

In addition, Dr. Chatterjee said, patients may now have “much higher” expectations for a smooth, symmetrical look “versus an outcome with excess skin and bumps.”

But Ms. Bowles said the desire for a more aesthetically pleasing look is nothing new.

“Women have always cared about how they look, they are just shamed into accepting a lesser result,” she argued. “If you look at why women go flat, the primary reason is they don’t want more surgery, not ‘I don’t care what I look like.’ ”

Three years after the mastectomy that left flaps of skin hanging from her chest, Ms. Bowles finally had a revision surgery to achieve the flat closure aesthetic she had wanted from the get-go.

“Nobody expects perfection, but I think the important thing is to have a standard of care that’s optimal,” said Ms. Bowles. “A patient like me should not have needed another surgery.”

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

Six years ago, Kim Bowles had a double mastectomy after being diagnosed with stage 3 breast cancer. Instead of opting for reconstruction, she decided to go “flat.” At 35, she had already breast fed both of her children, and didn’t want breasts anymore.

She asked her surgeon for an aesthetic flat closure, showing him photos of a smooth chest with no excess skin flaps. Although he agreed to her request in the office, he reneged in the operating room.

As the anesthesia took effect he said, “I’ll just leave a little extra skin, in case you change your mind.”

The last thing she remembers is telling him “no.”

When Ms. Bowles woke up, she saw excess tissue instead of the smooth chest she had requested. When she was eventually well enough, she staged a topless sit-in at the hospital and marched outside with a placard, baring her breastless, disfigured chest.

“Do I need a B-cup side-boob?” she asked, pulling at her lateral excess tissue, often referred to as dog ears. “You would never think that a surgeon would leave somebody looking like that,” she said in an interview.

Based on her experience, Ms. Bowles coined the term “flat denial” to describe what her surgeon did.
 

The weight of flat denial

In a recent study, Deanna Attai, MD, a breast surgeon at University of California, Los Angeles, discovered that more than one in five women who want a flat closure experience flat denial.

But well before that survey, Dr. Attai first came across flat denial more than a decade ago when a patient came to her for a second opinion after another surgeon insisted the patient see a psychiatrist when she requested a flat closure. Dr. Attai performed the flat closure for her instead.

But Dr. Attai said flat denial can take many forms. Some experiences may closely match the paternalistic encounter Ms. Bowles had, where a surgeon disregards a patient’s request. Other surgeons may simply be ignorant that a flat closure can be achieved aesthetically or that patients would even want this option.

This resistance aligns with Hester Schnipper’s experience as an oncology social worker. In her 45-year career, she has often found herself pushing back against breast surgeons who present reconstruction as if it were the only option for patients after mastectomy.

“And because most women are so overwhelmed, so scared, so stressed, they tend to go with whatever the doctor suggests,” said Ms. Schnipper.

Whatever form flat denial takes, the outcome can be damaging to the patient.

“This isn’t just ‘my scar’s a little thick.’ This is much more,” Dr. Attai said. “How do you even put a prosthesis on that? And if you’re not going to do a prosthesis in a bra, how do you even wear a shirt with all of that? It becomes a cleaning issue and depending on how things scar down you can get irregular fibrosis.”

What’s more, the harms of flat denial can extend beyond the physical scars.

Like Ms. Bowles, Anne Marie Champagne had made her desire for a flat closure clear to her surgeon before undergoing a mastectomy in 2009. The surgeon also reneged in the operating room while Champagne was unconscious and unable to object.

Ms. Champagne told The Washington Post that her surgeon’s justification for his actions left her feeling “profound grief, a combination of heartache and anger.

“I couldn’t believe that my surgeon would make a decision for me while I was under anesthesia that went against everything we had discussed – what I had consented to.”

Although it’s not clear how often women experience flat denial, discussions surrounding the issue have increased in recent years.

Ms. Bowles started a patient advocacy organization called “Not Putting on A Shirt” to help other women. And Dr. Attai moderates a Twitter group, called #BCSM or Breast Cancer Social Media, where patients share their experiences of breast cancer treatment, including in some cases flat denial.

“In getting to know so many women in the online space, an early observation was that the conversations online were different than what we had in the office,” Dr. Attai said. Online, “women were less guarded and more open about sharing the entirety of their breast cancer experience, including the more painful and raw moments.”

Being immersed in these moments, it also became clear to Dr. Attai that members of the treatment team don’t always recognize what is most important to a patient. “We might not ask, we might not allow them the time to express their preferences, or we might not really hear them,” she said.
 

An evolving awareness

National figures on the prevalence of flat closures remain elusive, but it has always been an option. And data indicate that many women choose no reconstruction after mastectomy.

One U.S. survey of women undergoing mastectomy between 2005 and 2007 found that 58% opted not to receive reconstruction, and a more recent British National Mastectomy and Breast Reconstruction Audit from 2011 found 70% chose no reconstruction.

“I definitely have seen more patients requesting to go flat after mastectomy, likely as they feel more empowered to make this decision,” Roshni Rao, MD, chief of breast surgery at Columbia University Medical Center, New York, told The Washington Post.

But to better understand the scope of flat denial, Dr. Attai and colleagues conducted a survey, published in Annals of Surgical Oncology. In it, she found that, among 931 women who had opted to go flat after mastectomy, 22% had experienced flat denial. That meant not being offered the option of going flat, not being supported in their choice to go flat, or not receiving the flat closure surgery initially agreed upon.

In the spring of 2022, Dr. Attai, past president of the American Society of Breast Surgeons, took her results to the society’s annual meeting. The goal was to bring to light aesthetic flat closure techniques as well as the harms of flat denial, presenting photos of the sagging, shriveled skin flaps alongside her analysis.

“No one ever goes into an operation intending it to look like those horrible pictures,” she said.

Asking for “no breast mound reconstruction” should imply a nice neat flat closure, or an aesthetic flat closure, Dr. Attai explained. “A patient should not have to specify she wants the surgeon to make all efforts to remove redundant and excess skin and fat, but I do think having the discussion and making preferences very clear is important, especially as we’ve seen that some patients are not getting the desired outcome.”

To help improve education and communication, the board of “No Putting on a Shirt” also had an exhibitor’s booth focused on aesthetic flat closures at the ASBrS meeting.

And given this growing awareness, the National Accreditation Program for Breast Centers has begun asking breast centers to report their process for shared decision-making on postmastectomy choices and provide proof that patients’ closure choices are being heard and followed.
 

A shift toward aesthetics

Despite a growing interest in flat closure aesthetics, the landscape shift is still relatively new.

The traditional mastectomy training Dr. Attai and colleagues went through in the 1990s did not emphasize aesthetics.

“I just removed the breast and then I left the room,” she said, explaining that the plastic surgeon took charge of the reconstruction. “We never really learned how to make a nice, neat closure.”

Abhishek Chatterjee, MD, MBA, a breast surgical oncologist and board-certified plastic surgeon, agreed that aesthetics have become more central in the field.

“A decade ago, I would argue that ... it wasn’t in the training program,” but today breast surgery fellowships now include “flat closures that are aesthetically appropriate,” said Dr. Chatterjee, who works at Tufts Medical Center in Boston and is vice chair of the ASBrS oncoplastics committee.

“In my mind, and in any surgeon’s mind, when you do something, you have to do it well ... and with that, aesthetics should be presumed,” he added.

But the term “aesthetic flat closure” was only adopted by the National Cancer Institute in 2020. The NCI, which considers an aesthetic flat closure reconstructive not cosmetic surgery, defines it as rebuilding the shape of the chest wall after breasts are removed, and involves contouring and eliminating excess tissue to create a smooth, flat chest wall.

Achieving this smooth look requires a skilled surgeon trained in flat closure reconstruction, which is not necessarily a guarantee. To help women find a surgeon, “Not Putting on A Shirt” has a flat friendly directory where patients can recommend surgeons who provide aesthetic flat closures. As of August 2022, the list has now grown to over 300 surgeons.

Dr. Chatterjee said the ASBrS is actively involved in training surgeons in aesthetic flat closure. Given this shift, he said most general or breast surgeons should have the skill set to design mastectomy flaps that enable a flat closure with no excess skin, but there are some caveats.

For instance, he noted, if a woman has a lot of breast tissue and excess skin in the outer, lateral folds of the axilla, “it is very, very hard to get a flat closure” and in those rare circumstances, a breast surgeon may need assistance from a plastic surgeon.

But Dr. Attai found a significant gap still exists between what should be done and what is being done in practice.

Part of that disconnect may stem from the lack of a standard of care.

In a recent publication, a team of plastic surgeons from New York University noted that, to date, “there is no plastic surgery literature on specific techniques to achieve an aesthetic flat closure after mastectomy.”

And Dr. Attai added, “there is really no way to know at this point what women are getting when they choose no breast mound reconstruction.”

Physicians may also simply not understand what their patients want.

Dr. Attai said she was “blown away” by the reaction to her presentation on flat denial at ASBrS in April. “I had a lot of members come up to me afterwards and say ‘I had no idea that patients would want this. I am guilty of not offering this.’ ”

In addition, Dr. Chatterjee said, patients may now have “much higher” expectations for a smooth, symmetrical look “versus an outcome with excess skin and bumps.”

But Ms. Bowles said the desire for a more aesthetically pleasing look is nothing new.

“Women have always cared about how they look, they are just shamed into accepting a lesser result,” she argued. “If you look at why women go flat, the primary reason is they don’t want more surgery, not ‘I don’t care what I look like.’ ”

Three years after the mastectomy that left flaps of skin hanging from her chest, Ms. Bowles finally had a revision surgery to achieve the flat closure aesthetic she had wanted from the get-go.

“Nobody expects perfection, but I think the important thing is to have a standard of care that’s optimal,” said Ms. Bowles. “A patient like me should not have needed another surgery.”

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

Healthy children who are underweight in the first 2 years of life continue with a lower-than-average body mass index and height-for-age through age 10, according to new research.

The association was most pronounced for girls, as well as for children with lower growth rates, write the authors of the prospective Canadian cohort study published in JAMA Network Open.

The findings “highlight the importance of preventing underweight in early life,” because this can have “lasting effects” in later childhood, senior author Jonathon L. Maguire, MD, from St Michael’s Hospital Pediatric Clinic, and the University of Toronto said in an interview.
 

Methods and results

The study recruited 5,803 healthy children, mean age 4.07 months, between February 2008 and September 2020 during well-child visits at clinics in The Applied Research Group for Kids! (TARGet Kids!) practice-based research network in Canada. The study’s exclusion criteria included a premature birth, or a health condition affecting growth.

The primary outcome of the study was the child’s age- and sex-adjusted weight, also known as the body mass index z score (zBMI), between the ages of 2 and 10 years.

At baseline, a total of 550 children (9.5%) were classified as underweight, based on the World Health Organization definition of zBMI less than –2. Underweight children were more likely to be younger, have lower birth weight, and to report Asian maternal ethnicity, the researchers observed.

The study found that, compared with children with normal weight, those who were underweight in the first 2 years had lower zBMI at ages 5 and 10 years (–0.49 and –0.39 respectively). This meant that at 10 years old, they were a mean of 1.23 kg lighter than 10-year-olds who had been normal weight at age 2 years.

Height-for-age z score (HAZ) was also lower for underweight 2-year-olds (–0.24), making them a mean of 0.68 cm shorter than normal-weight 2-year-olds. This difference was attenuated at age 5 years.

Growth rate modified the association of underweight with both zBMI and HAZ. Among children who were underweight in the first 2 years, those with lower growth rate had lower zBMI at 10 years (–0.64) compared with those with average (–0.38) or high growth rate (0.11). Similarly, children who were underweight and had a lower growth rate at age 2 years also a lower HAZ at age 10 years (–0.12), compared with those with average (0.02) or high growth rates (0.16). These effects were more pronounced in girls.
 

Increased health risks linked with chronic underweight

This study did not assess the reasons for early underweight, Dr. Maguire commented in an interview. But, he cited challenges with dietary transitions as a possible explanation.

“Considerable dietary changes happen around 2 years of age with increasing diversity of foods as children transition from primarily liquid foods to primarily solid foods,” he noted.

Asked for comment on the study, Colleen Spees, PhD, associate professor in the division of medical dietetics and director of Hope lab at the Ohio State University, Columbus, said that “at age 10, it’s not surprising to see a lower zBMI and height-for-age in those that were underweight at age 2 with poor growth trajectories.”

Although, this is the first study she is aware of to document these findings in a Canadian cohort, “the results align with what we know about low birth weight and underweight infants and children in terms of linear growth trajectories from child stunting studies,” Dr. Spees said.

She said child stunting, which is more common in less developed countries where children have lower birth weights and greater socioeconomic and environmental risk factors, is defined by the WHO as impaired linear growth with adverse functional consequences.

“In short, a chronic underweight status in infants and young children can lead to greater risk of malnutrition, vitamin and mineral deficiencies, decreased immune function, as well as physical growth and development issues,” she said. “Hence, the most recent 2020-2025 Dietary Guidelines for Americans now includes both pregnancy, breastfeeding, and the first 2 years of life (referred to as the “first 1,000 days”) in their recommendations.”

She added that, if caregivers are concerned about their child’s weight, they should consult with their pediatrician to rule out any medical issues. If no medical issues are identified, they should ask for a referral to a pediatric dietitian.

The study was funded by the Canadian Institute of Health Research. Dr Maguire reported receiving grants from the CIHR, Physician Services, Ontario SPOR Support Unit, and Dairy Farmers of Canada during the conduct of the study and nonfinancial support from DDrops outside the submitted work. Other authors of the paper reported receiving grants from various institutions. Dr. Spees reported no relevant disclosures.

Healthy children who are underweight in the first 2 years of life continue with a lower-than-average body mass index and height-for-age through age 10, according to new research.

The association was most pronounced for girls, as well as for children with lower growth rates, write the authors of the prospective Canadian cohort study published in JAMA Network Open.

The findings “highlight the importance of preventing underweight in early life,” because this can have “lasting effects” in later childhood, senior author Jonathon L. Maguire, MD, from St Michael’s Hospital Pediatric Clinic, and the University of Toronto said in an interview.
 

Methods and results

The study recruited 5,803 healthy children, mean age 4.07 months, between February 2008 and September 2020 during well-child visits at clinics in The Applied Research Group for Kids! (TARGet Kids!) practice-based research network in Canada. The study’s exclusion criteria included a premature birth, or a health condition affecting growth.

The primary outcome of the study was the child’s age- and sex-adjusted weight, also known as the body mass index z score (zBMI), between the ages of 2 and 10 years.

At baseline, a total of 550 children (9.5%) were classified as underweight, based on the World Health Organization definition of zBMI less than –2. Underweight children were more likely to be younger, have lower birth weight, and to report Asian maternal ethnicity, the researchers observed.

The study found that, compared with children with normal weight, those who were underweight in the first 2 years had lower zBMI at ages 5 and 10 years (–0.49 and –0.39 respectively). This meant that at 10 years old, they were a mean of 1.23 kg lighter than 10-year-olds who had been normal weight at age 2 years.

Height-for-age z score (HAZ) was also lower for underweight 2-year-olds (–0.24), making them a mean of 0.68 cm shorter than normal-weight 2-year-olds. This difference was attenuated at age 5 years.

Growth rate modified the association of underweight with both zBMI and HAZ. Among children who were underweight in the first 2 years, those with lower growth rate had lower zBMI at 10 years (–0.64) compared with those with average (–0.38) or high growth rate (0.11). Similarly, children who were underweight and had a lower growth rate at age 2 years also a lower HAZ at age 10 years (–0.12), compared with those with average (0.02) or high growth rates (0.16). These effects were more pronounced in girls.
 

Increased health risks linked with chronic underweight

This study did not assess the reasons for early underweight, Dr. Maguire commented in an interview. But, he cited challenges with dietary transitions as a possible explanation.

“Considerable dietary changes happen around 2 years of age with increasing diversity of foods as children transition from primarily liquid foods to primarily solid foods,” he noted.

Asked for comment on the study, Colleen Spees, PhD, associate professor in the division of medical dietetics and director of Hope lab at the Ohio State University, Columbus, said that “at age 10, it’s not surprising to see a lower zBMI and height-for-age in those that were underweight at age 2 with poor growth trajectories.”

Although, this is the first study she is aware of to document these findings in a Canadian cohort, “the results align with what we know about low birth weight and underweight infants and children in terms of linear growth trajectories from child stunting studies,” Dr. Spees said.

She said child stunting, which is more common in less developed countries where children have lower birth weights and greater socioeconomic and environmental risk factors, is defined by the WHO as impaired linear growth with adverse functional consequences.

“In short, a chronic underweight status in infants and young children can lead to greater risk of malnutrition, vitamin and mineral deficiencies, decreased immune function, as well as physical growth and development issues,” she said. “Hence, the most recent 2020-2025 Dietary Guidelines for Americans now includes both pregnancy, breastfeeding, and the first 2 years of life (referred to as the “first 1,000 days”) in their recommendations.”

She added that, if caregivers are concerned about their child’s weight, they should consult with their pediatrician to rule out any medical issues. If no medical issues are identified, they should ask for a referral to a pediatric dietitian.

The study was funded by the Canadian Institute of Health Research. Dr Maguire reported receiving grants from the CIHR, Physician Services, Ontario SPOR Support Unit, and Dairy Farmers of Canada during the conduct of the study and nonfinancial support from DDrops outside the submitted work. Other authors of the paper reported receiving grants from various institutions. Dr. Spees reported no relevant disclosures.

Healthy children who are underweight in the first 2 years of life continue with a lower-than-average body mass index and height-for-age through age 10, according to new research.

The association was most pronounced for girls, as well as for children with lower growth rates, write the authors of the prospective Canadian cohort study published in JAMA Network Open.

The findings “highlight the importance of preventing underweight in early life,” because this can have “lasting effects” in later childhood, senior author Jonathon L. Maguire, MD, from St Michael’s Hospital Pediatric Clinic, and the University of Toronto said in an interview.
 

Methods and results

The study recruited 5,803 healthy children, mean age 4.07 months, between February 2008 and September 2020 during well-child visits at clinics in The Applied Research Group for Kids! (TARGet Kids!) practice-based research network in Canada. The study’s exclusion criteria included a premature birth, or a health condition affecting growth.

The primary outcome of the study was the child’s age- and sex-adjusted weight, also known as the body mass index z score (zBMI), between the ages of 2 and 10 years.

At baseline, a total of 550 children (9.5%) were classified as underweight, based on the World Health Organization definition of zBMI less than –2. Underweight children were more likely to be younger, have lower birth weight, and to report Asian maternal ethnicity, the researchers observed.

The study found that, compared with children with normal weight, those who were underweight in the first 2 years had lower zBMI at ages 5 and 10 years (–0.49 and –0.39 respectively). This meant that at 10 years old, they were a mean of 1.23 kg lighter than 10-year-olds who had been normal weight at age 2 years.

Height-for-age z score (HAZ) was also lower for underweight 2-year-olds (–0.24), making them a mean of 0.68 cm shorter than normal-weight 2-year-olds. This difference was attenuated at age 5 years.

Growth rate modified the association of underweight with both zBMI and HAZ. Among children who were underweight in the first 2 years, those with lower growth rate had lower zBMI at 10 years (–0.64) compared with those with average (–0.38) or high growth rate (0.11). Similarly, children who were underweight and had a lower growth rate at age 2 years also a lower HAZ at age 10 years (–0.12), compared with those with average (0.02) or high growth rates (0.16). These effects were more pronounced in girls.
 

Increased health risks linked with chronic underweight

This study did not assess the reasons for early underweight, Dr. Maguire commented in an interview. But, he cited challenges with dietary transitions as a possible explanation.

“Considerable dietary changes happen around 2 years of age with increasing diversity of foods as children transition from primarily liquid foods to primarily solid foods,” he noted.

Asked for comment on the study, Colleen Spees, PhD, associate professor in the division of medical dietetics and director of Hope lab at the Ohio State University, Columbus, said that “at age 10, it’s not surprising to see a lower zBMI and height-for-age in those that were underweight at age 2 with poor growth trajectories.”

Although, this is the first study she is aware of to document these findings in a Canadian cohort, “the results align with what we know about low birth weight and underweight infants and children in terms of linear growth trajectories from child stunting studies,” Dr. Spees said.

She said child stunting, which is more common in less developed countries where children have lower birth weights and greater socioeconomic and environmental risk factors, is defined by the WHO as impaired linear growth with adverse functional consequences.

“In short, a chronic underweight status in infants and young children can lead to greater risk of malnutrition, vitamin and mineral deficiencies, decreased immune function, as well as physical growth and development issues,” she said. “Hence, the most recent 2020-2025 Dietary Guidelines for Americans now includes both pregnancy, breastfeeding, and the first 2 years of life (referred to as the “first 1,000 days”) in their recommendations.”

She added that, if caregivers are concerned about their child’s weight, they should consult with their pediatrician to rule out any medical issues. If no medical issues are identified, they should ask for a referral to a pediatric dietitian.

The study was funded by the Canadian Institute of Health Research. Dr Maguire reported receiving grants from the CIHR, Physician Services, Ontario SPOR Support Unit, and Dairy Farmers of Canada during the conduct of the study and nonfinancial support from DDrops outside the submitted work. Other authors of the paper reported receiving grants from various institutions. Dr. Spees reported no relevant disclosures.

MONTREAL – Long-acting, injectable cabotegravir (CAB LA) continues to show superiority over oral daily tenofovir diphosphate plus emtricitabine (TDF-FTC) as preexposure prophylaxis (PrEP) for HIV, according to new data from two HIV Prevention Trials Network (HPTN) studies reported at the International AIDS Society Conference.

Follow-up data from the HPTN 084 trial, which compared the two regimens in 3,224 sub-Saharan persons who were assigned female sex at birth, show that three new HIV infections occurred in the CAB LA group in the 12 months since the study was unblinded, versus 20 new infections among the TDF-FTC group. That translates to an 89% lower risk of infection in the CAB LA arm across both the blinded and unblinded phases of the trial, said lead investigator Sinead Delany-Moretlwe, MD, PhD, director of research, Wits Reproductive Health and HIV Institute, the University of the Witwatersrand, Johannesburg, South Africa, during a press conference.

“The trial was designed with the assumption that both drugs were highly effective in preventing HIV infection but that, given the challenges with taking a pill a day, that injectable cabotegravir may offer an adherence advantage,” she said in an interview. “Our data appear to confirm this, as most of the participants in the TDF-FTC arm who became infected with HIV had evidence of poor or inconsistent use of PrEP.”

The study also found that pregnancy incidence increased “two- to threefold” between the blinded and the unblinded period, “and this emphasizes to us the desire of women to conceive safely, without the threat of HIV, and the importance of us continuing to evaluate the safety and pharmacology of cabotegravir in pregnant and breastfeeding women during open-label extension phase of HPTN 084, so that [they] are not excluded from access to this highly effective PrEP agent,” she said. To date, no congenital anomalies have been reported in babies born during the study.

In an update report from HPTN 083, which also showed superiority of CAB LA over TDF-FTC in cisgender men and transgender women (TGW), researchers reported the safety and efficacy of CAB LA use in TGW using gender-affirming hormone therapy (GAHT).

Among the 4,566 participants in HPTN 083, 570 were TGW, and of those, 58% used GAHT at baseline, reported Beatriz Grinsztejn, MD, PhD, head of the STD/AIDS Clinical Research Laboratory at the Instituto Nacional de Infectologicia/Fundação Oswaldo Cruz.

CAB LA drug concentrations measured in a subset of 53 TGW who received on-time CAB injections were comparable between those taking (n = 30) and those not taking GAHT (n = 23), “suggesting the lack of a gender-affirming hormone effect on CAB pharmacokinetics,” she said. “These are very promising results, as we all know that the use of gender-affirming hormone therapy is a major priority for our transgender women community, ... so the lack of drug-drug interaction is really a very important result.”

“Cabotegravir long-acting PrEP is now approved for all at-risk populations, including men who have sex with men, transgender women, and cisgender women, after the results of HPTN 083 and 084,” commented Monica Gandhi, MD, MPH, an infectious disease physician, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco (UCSF).

Dr. Gandhi, who was not involved in either study, is also director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “The incredible efficacy of long-acting PrEP for cisgender women shown by HPTN 084 is game-changing for our practice, and we have already instituted CAB LA across a range of populations at Ward 86,” she said in an interview. “The durability of the 89% additional efficacy of CAB LA over oral TDF/FTC is thrilling and will lead to a greater use of long-acting options.”

She acknowledged that information on potential interactions of GAHT was needed from the HPTN 083 trial. “That cabotegravir levels did not change with the use of estradiol or spironolactone for gender-affirming therapy is important news for our practice and to reassure our TGW that they can safely and effectively use CAB LA for HIV prevention.”

The HPTN 084 and 083 trials were funded by the National Institutes for Allergy and Infectious Diseases. Dr. Delany-Moretlwe, Dr. Grinsztejn, and Dr. Gandhi have disclosed no relevant financial relationships.

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

MONTREAL – Long-acting, injectable cabotegravir (CAB LA) continues to show superiority over oral daily tenofovir diphosphate plus emtricitabine (TDF-FTC) as preexposure prophylaxis (PrEP) for HIV, according to new data from two HIV Prevention Trials Network (HPTN) studies reported at the International AIDS Society Conference.

Follow-up data from the HPTN 084 trial, which compared the two regimens in 3,224 sub-Saharan persons who were assigned female sex at birth, show that three new HIV infections occurred in the CAB LA group in the 12 months since the study was unblinded, versus 20 new infections among the TDF-FTC group. That translates to an 89% lower risk of infection in the CAB LA arm across both the blinded and unblinded phases of the trial, said lead investigator Sinead Delany-Moretlwe, MD, PhD, director of research, Wits Reproductive Health and HIV Institute, the University of the Witwatersrand, Johannesburg, South Africa, during a press conference.

“The trial was designed with the assumption that both drugs were highly effective in preventing HIV infection but that, given the challenges with taking a pill a day, that injectable cabotegravir may offer an adherence advantage,” she said in an interview. “Our data appear to confirm this, as most of the participants in the TDF-FTC arm who became infected with HIV had evidence of poor or inconsistent use of PrEP.”

The study also found that pregnancy incidence increased “two- to threefold” between the blinded and the unblinded period, “and this emphasizes to us the desire of women to conceive safely, without the threat of HIV, and the importance of us continuing to evaluate the safety and pharmacology of cabotegravir in pregnant and breastfeeding women during open-label extension phase of HPTN 084, so that [they] are not excluded from access to this highly effective PrEP agent,” she said. To date, no congenital anomalies have been reported in babies born during the study.

In an update report from HPTN 083, which also showed superiority of CAB LA over TDF-FTC in cisgender men and transgender women (TGW), researchers reported the safety and efficacy of CAB LA use in TGW using gender-affirming hormone therapy (GAHT).

Among the 4,566 participants in HPTN 083, 570 were TGW, and of those, 58% used GAHT at baseline, reported Beatriz Grinsztejn, MD, PhD, head of the STD/AIDS Clinical Research Laboratory at the Instituto Nacional de Infectologicia/Fundação Oswaldo Cruz.

CAB LA drug concentrations measured in a subset of 53 TGW who received on-time CAB injections were comparable between those taking (n = 30) and those not taking GAHT (n = 23), “suggesting the lack of a gender-affirming hormone effect on CAB pharmacokinetics,” she said. “These are very promising results, as we all know that the use of gender-affirming hormone therapy is a major priority for our transgender women community, ... so the lack of drug-drug interaction is really a very important result.”

“Cabotegravir long-acting PrEP is now approved for all at-risk populations, including men who have sex with men, transgender women, and cisgender women, after the results of HPTN 083 and 084,” commented Monica Gandhi, MD, MPH, an infectious disease physician, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco (UCSF).

Dr. Gandhi, who was not involved in either study, is also director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “The incredible efficacy of long-acting PrEP for cisgender women shown by HPTN 084 is game-changing for our practice, and we have already instituted CAB LA across a range of populations at Ward 86,” she said in an interview. “The durability of the 89% additional efficacy of CAB LA over oral TDF/FTC is thrilling and will lead to a greater use of long-acting options.”

She acknowledged that information on potential interactions of GAHT was needed from the HPTN 083 trial. “That cabotegravir levels did not change with the use of estradiol or spironolactone for gender-affirming therapy is important news for our practice and to reassure our TGW that they can safely and effectively use CAB LA for HIV prevention.”

The HPTN 084 and 083 trials were funded by the National Institutes for Allergy and Infectious Diseases. Dr. Delany-Moretlwe, Dr. Grinsztejn, and Dr. Gandhi have disclosed no relevant financial relationships.

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

MONTREAL – Long-acting, injectable cabotegravir (CAB LA) continues to show superiority over oral daily tenofovir diphosphate plus emtricitabine (TDF-FTC) as preexposure prophylaxis (PrEP) for HIV, according to new data from two HIV Prevention Trials Network (HPTN) studies reported at the International AIDS Society Conference.

Follow-up data from the HPTN 084 trial, which compared the two regimens in 3,224 sub-Saharan persons who were assigned female sex at birth, show that three new HIV infections occurred in the CAB LA group in the 12 months since the study was unblinded, versus 20 new infections among the TDF-FTC group. That translates to an 89% lower risk of infection in the CAB LA arm across both the blinded and unblinded phases of the trial, said lead investigator Sinead Delany-Moretlwe, MD, PhD, director of research, Wits Reproductive Health and HIV Institute, the University of the Witwatersrand, Johannesburg, South Africa, during a press conference.

“The trial was designed with the assumption that both drugs were highly effective in preventing HIV infection but that, given the challenges with taking a pill a day, that injectable cabotegravir may offer an adherence advantage,” she said in an interview. “Our data appear to confirm this, as most of the participants in the TDF-FTC arm who became infected with HIV had evidence of poor or inconsistent use of PrEP.”

The study also found that pregnancy incidence increased “two- to threefold” between the blinded and the unblinded period, “and this emphasizes to us the desire of women to conceive safely, without the threat of HIV, and the importance of us continuing to evaluate the safety and pharmacology of cabotegravir in pregnant and breastfeeding women during open-label extension phase of HPTN 084, so that [they] are not excluded from access to this highly effective PrEP agent,” she said. To date, no congenital anomalies have been reported in babies born during the study.

In an update report from HPTN 083, which also showed superiority of CAB LA over TDF-FTC in cisgender men and transgender women (TGW), researchers reported the safety and efficacy of CAB LA use in TGW using gender-affirming hormone therapy (GAHT).

Among the 4,566 participants in HPTN 083, 570 were TGW, and of those, 58% used GAHT at baseline, reported Beatriz Grinsztejn, MD, PhD, head of the STD/AIDS Clinical Research Laboratory at the Instituto Nacional de Infectologicia/Fundação Oswaldo Cruz.

CAB LA drug concentrations measured in a subset of 53 TGW who received on-time CAB injections were comparable between those taking (n = 30) and those not taking GAHT (n = 23), “suggesting the lack of a gender-affirming hormone effect on CAB pharmacokinetics,” she said. “These are very promising results, as we all know that the use of gender-affirming hormone therapy is a major priority for our transgender women community, ... so the lack of drug-drug interaction is really a very important result.”

“Cabotegravir long-acting PrEP is now approved for all at-risk populations, including men who have sex with men, transgender women, and cisgender women, after the results of HPTN 083 and 084,” commented Monica Gandhi, MD, MPH, an infectious disease physician, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco (UCSF).

Dr. Gandhi, who was not involved in either study, is also director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “The incredible efficacy of long-acting PrEP for cisgender women shown by HPTN 084 is game-changing for our practice, and we have already instituted CAB LA across a range of populations at Ward 86,” she said in an interview. “The durability of the 89% additional efficacy of CAB LA over oral TDF/FTC is thrilling and will lead to a greater use of long-acting options.”

She acknowledged that information on potential interactions of GAHT was needed from the HPTN 083 trial. “That cabotegravir levels did not change with the use of estradiol or spironolactone for gender-affirming therapy is important news for our practice and to reassure our TGW that they can safely and effectively use CAB LA for HIV prevention.”

The HPTN 084 and 083 trials were funded by the National Institutes for Allergy and Infectious Diseases. Dr. Delany-Moretlwe, Dr. Grinsztejn, and Dr. Gandhi have disclosed no relevant financial relationships.

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.

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 – One 200-mg dose of doxycycline taken as postexposure prophylaxis (PEP) reduced the incidence of three sexually transmitted infections (STIs) by 65% among men who have sex with men (MSM) and transgender women (TGW) living with HIV or taking preexposure prophylaxis (PrEP). The results of the open-label DoxyPEP trial were reported at a press conference at a meeting of the International AIDS Society.

“It is time to take action on the data that we have and really think about incorporating it into guidelines and rolling this out in a safe and thoughtful way,” said co-principal investigator Annie Luetkemeyer, MD, of Zuckerberg San Francisco General Hospital, and professor of medicine at the University of California, San Francisco (UCSF).

The open-label trial, conducted in Seattle and San Francisco, randomized MSM/TGW living with HIV or on PrEP, and with a history of N. gonorrhoeae (GC), C. trachomatis (CT), or early syphilis in the past year, to either doxycycline or none within 72 hours of having condomless sex. It was stopped early in May when a planned interim analysis showed those randomized to take doxycycline had substantially fewer STIs than participants assigned to the control group.

The intent-to-treat analysis included 501 patients with at least one quarter of follow-up: 327 taking PrEP and 174 living with HIV. Among those taking PrEP, new STIs (GC, CT or syphilis) occurred in 31.9% of control participants vs. 10.7% of those taking doxycycline – a reduction of 66% per quarter (P < .001). Among participants living with HIV, new STIs occurred in 30.5% of controls vs. 11.8% taking doxycycline, for a 62% reduction in STIs per quarter (P < .0001).

“Participants reported taking doxycycline 87% of the time after having condomless sex, about half of participants took fewer than 10 doses per month, 30% took 10-20 doses per month, and 16% took more than 20 doses of doxycycline per month,” said Dr. Luetkemeyer, adding that there were no serious – grade 2 or greater – adverse events, and “the majority of participants reported that taking doxy was acceptable or very acceptable.”

Asked how broadly doxycycline prophylaxis could be used in other populations, Dr. Luetkemeyer was cautious. “Our study participants had a very high rate of new STIs – a 30% incidence per quarter  and using doxyPEP was well tolerated and very effective to reduce new STIs. However, this is a fairly limited population,” she said. “Whether doxyPEP should be considered for other groups, such as women on PrEP or with an elevated risk for STIs, will need more data which will be forthcoming from ongoing studies.”  

Dr. Luetkemeyer said her group is looking at three possible risks of antibiotic resistance with the doxyPEP regimen: the risk to bystander bacteria such as Staphylococcus aureus or commensal neisseria; the impact on the gut; and the risk of resistance to antibiotic treatments for STI.

For the latter, “we don’t really think this is going to be an issue in chlamydia and syphilis, and we’re looking carefully at gonorrhea,” she said, adding that it will be challenging to get definitive data from this particular study because of its short follow-up.

“Available culture data from those who had gonorrhea infections during the study demonstrated a relatively low rate of tetracycline resistance, which is a proxy for doxycycline resistance, at 20%. ... However, larger studies and population-based surveillance of those taking doxycycline as PEP are needed to understand if doxycycline use could drive the element of tetracycline resistance in gonorrhea,” she said, emphasizing that doxycycline is not used to treat active gonorrhea infections.

Calling the doxyPEP regimen a  “game-changing strategy,” Sharon Lewin, AO, PhD, president-elect of the International AIDS Society, said many physicians are already prescribing it off label based on the IPERGAY study (N Engl J Med. 2015; 373:2237-46) “but there’s a clear need for more evidence to guide the use of this intervention.”

“This study has huge implications for clinical care,” said Monica Gandhi, MD, MPH, an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at UCSF. “Although the data on drug resistance is very important to evaluate, we should certainly consider at this point using doxycycline PEP within 72 hours of condomless sex for our patients for STI prevention,” she said in an interview.

“In our practice, we are very excited about the possibility of a simple one-pill postexposure prophylactic agent (doxycycline 200 mg) to reduce the risk of a number of STIs. We have used PEP for HIV infection for a number of years and are very familiar with the concept of preventing infections after an exposure,” said Dr. Gandhi, director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “We are planning to institute doxycycline as PEP at my clinic after the release of these findings and will follow the remainder of the study findings closely.”

The trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, through grant R01AI143439. It was conducted at the HIV clinic at Zuckerberg San Francisco General Hospital and the San Francisco City Clinic, both part of the San Francisco Department of Public Health, and the Madison Clinic and the Sexual Health Clinic at Harborview Medical Center, both at the University of Washington. Medications were provided by Mayne Pharmaceuticals, and lab support by Hologic & Cepheid.

Dr. Lewin has the following disclosures: investigator-initiated, industry-funded research for Gilead, Viiv, Merck; scientific advisory board (honoraria paid to her personally) for Gilead, Merck, Viiv, Esfam, Immunocore, Vaxxinity; collaborative research (nonfunded) for AbbVie, Genentech, BMS. Dr. Luetkemeyer and Dr. Gandhi reported no relevant financial relationships.

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

MONTREAL – One 200-mg dose of doxycycline taken as postexposure prophylaxis (PEP) reduced the incidence of three sexually transmitted infections (STIs) by 65% among men who have sex with men (MSM) and transgender women (TGW) living with HIV or taking preexposure prophylaxis (PrEP). The results of the open-label DoxyPEP trial were reported at a press conference at a meeting of the International AIDS Society.

“It is time to take action on the data that we have and really think about incorporating it into guidelines and rolling this out in a safe and thoughtful way,” said co-principal investigator Annie Luetkemeyer, MD, of Zuckerberg San Francisco General Hospital, and professor of medicine at the University of California, San Francisco (UCSF).

The open-label trial, conducted in Seattle and San Francisco, randomized MSM/TGW living with HIV or on PrEP, and with a history of N. gonorrhoeae (GC), C. trachomatis (CT), or early syphilis in the past year, to either doxycycline or none within 72 hours of having condomless sex. It was stopped early in May when a planned interim analysis showed those randomized to take doxycycline had substantially fewer STIs than participants assigned to the control group.

The intent-to-treat analysis included 501 patients with at least one quarter of follow-up: 327 taking PrEP and 174 living with HIV. Among those taking PrEP, new STIs (GC, CT or syphilis) occurred in 31.9% of control participants vs. 10.7% of those taking doxycycline – a reduction of 66% per quarter (P < .001). Among participants living with HIV, new STIs occurred in 30.5% of controls vs. 11.8% taking doxycycline, for a 62% reduction in STIs per quarter (P < .0001).

“Participants reported taking doxycycline 87% of the time after having condomless sex, about half of participants took fewer than 10 doses per month, 30% took 10-20 doses per month, and 16% took more than 20 doses of doxycycline per month,” said Dr. Luetkemeyer, adding that there were no serious – grade 2 or greater – adverse events, and “the majority of participants reported that taking doxy was acceptable or very acceptable.”

Asked how broadly doxycycline prophylaxis could be used in other populations, Dr. Luetkemeyer was cautious. “Our study participants had a very high rate of new STIs – a 30% incidence per quarter  and using doxyPEP was well tolerated and very effective to reduce new STIs. However, this is a fairly limited population,” she said. “Whether doxyPEP should be considered for other groups, such as women on PrEP or with an elevated risk for STIs, will need more data which will be forthcoming from ongoing studies.”  

Dr. Luetkemeyer said her group is looking at three possible risks of antibiotic resistance with the doxyPEP regimen: the risk to bystander bacteria such as Staphylococcus aureus or commensal neisseria; the impact on the gut; and the risk of resistance to antibiotic treatments for STI.

For the latter, “we don’t really think this is going to be an issue in chlamydia and syphilis, and we’re looking carefully at gonorrhea,” she said, adding that it will be challenging to get definitive data from this particular study because of its short follow-up.

“Available culture data from those who had gonorrhea infections during the study demonstrated a relatively low rate of tetracycline resistance, which is a proxy for doxycycline resistance, at 20%. ... However, larger studies and population-based surveillance of those taking doxycycline as PEP are needed to understand if doxycycline use could drive the element of tetracycline resistance in gonorrhea,” she said, emphasizing that doxycycline is not used to treat active gonorrhea infections.

Calling the doxyPEP regimen a  “game-changing strategy,” Sharon Lewin, AO, PhD, president-elect of the International AIDS Society, said many physicians are already prescribing it off label based on the IPERGAY study (N Engl J Med. 2015; 373:2237-46) “but there’s a clear need for more evidence to guide the use of this intervention.”

“This study has huge implications for clinical care,” said Monica Gandhi, MD, MPH, an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at UCSF. “Although the data on drug resistance is very important to evaluate, we should certainly consider at this point using doxycycline PEP within 72 hours of condomless sex for our patients for STI prevention,” she said in an interview.

“In our practice, we are very excited about the possibility of a simple one-pill postexposure prophylactic agent (doxycycline 200 mg) to reduce the risk of a number of STIs. We have used PEP for HIV infection for a number of years and are very familiar with the concept of preventing infections after an exposure,” said Dr. Gandhi, director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “We are planning to institute doxycycline as PEP at my clinic after the release of these findings and will follow the remainder of the study findings closely.”

The trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, through grant R01AI143439. It was conducted at the HIV clinic at Zuckerberg San Francisco General Hospital and the San Francisco City Clinic, both part of the San Francisco Department of Public Health, and the Madison Clinic and the Sexual Health Clinic at Harborview Medical Center, both at the University of Washington. Medications were provided by Mayne Pharmaceuticals, and lab support by Hologic & Cepheid.

Dr. Lewin has the following disclosures: investigator-initiated, industry-funded research for Gilead, Viiv, Merck; scientific advisory board (honoraria paid to her personally) for Gilead, Merck, Viiv, Esfam, Immunocore, Vaxxinity; collaborative research (nonfunded) for AbbVie, Genentech, BMS. Dr. Luetkemeyer and Dr. Gandhi reported no relevant financial relationships.

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

MONTREAL – One 200-mg dose of doxycycline taken as postexposure prophylaxis (PEP) reduced the incidence of three sexually transmitted infections (STIs) by 65% among men who have sex with men (MSM) and transgender women (TGW) living with HIV or taking preexposure prophylaxis (PrEP). The results of the open-label DoxyPEP trial were reported at a press conference at a meeting of the International AIDS Society.

“It is time to take action on the data that we have and really think about incorporating it into guidelines and rolling this out in a safe and thoughtful way,” said co-principal investigator Annie Luetkemeyer, MD, of Zuckerberg San Francisco General Hospital, and professor of medicine at the University of California, San Francisco (UCSF).

The open-label trial, conducted in Seattle and San Francisco, randomized MSM/TGW living with HIV or on PrEP, and with a history of N. gonorrhoeae (GC), C. trachomatis (CT), or early syphilis in the past year, to either doxycycline or none within 72 hours of having condomless sex. It was stopped early in May when a planned interim analysis showed those randomized to take doxycycline had substantially fewer STIs than participants assigned to the control group.

The intent-to-treat analysis included 501 patients with at least one quarter of follow-up: 327 taking PrEP and 174 living with HIV. Among those taking PrEP, new STIs (GC, CT or syphilis) occurred in 31.9% of control participants vs. 10.7% of those taking doxycycline – a reduction of 66% per quarter (P < .001). Among participants living with HIV, new STIs occurred in 30.5% of controls vs. 11.8% taking doxycycline, for a 62% reduction in STIs per quarter (P < .0001).

“Participants reported taking doxycycline 87% of the time after having condomless sex, about half of participants took fewer than 10 doses per month, 30% took 10-20 doses per month, and 16% took more than 20 doses of doxycycline per month,” said Dr. Luetkemeyer, adding that there were no serious – grade 2 or greater – adverse events, and “the majority of participants reported that taking doxy was acceptable or very acceptable.”

Asked how broadly doxycycline prophylaxis could be used in other populations, Dr. Luetkemeyer was cautious. “Our study participants had a very high rate of new STIs – a 30% incidence per quarter  and using doxyPEP was well tolerated and very effective to reduce new STIs. However, this is a fairly limited population,” she said. “Whether doxyPEP should be considered for other groups, such as women on PrEP or with an elevated risk for STIs, will need more data which will be forthcoming from ongoing studies.”  

Dr. Luetkemeyer said her group is looking at three possible risks of antibiotic resistance with the doxyPEP regimen: the risk to bystander bacteria such as Staphylococcus aureus or commensal neisseria; the impact on the gut; and the risk of resistance to antibiotic treatments for STI.

For the latter, “we don’t really think this is going to be an issue in chlamydia and syphilis, and we’re looking carefully at gonorrhea,” she said, adding that it will be challenging to get definitive data from this particular study because of its short follow-up.

“Available culture data from those who had gonorrhea infections during the study demonstrated a relatively low rate of tetracycline resistance, which is a proxy for doxycycline resistance, at 20%. ... However, larger studies and population-based surveillance of those taking doxycycline as PEP are needed to understand if doxycycline use could drive the element of tetracycline resistance in gonorrhea,” she said, emphasizing that doxycycline is not used to treat active gonorrhea infections.

Calling the doxyPEP regimen a  “game-changing strategy,” Sharon Lewin, AO, PhD, president-elect of the International AIDS Society, said many physicians are already prescribing it off label based on the IPERGAY study (N Engl J Med. 2015; 373:2237-46) “but there’s a clear need for more evidence to guide the use of this intervention.”

“This study has huge implications for clinical care,” said Monica Gandhi, MD, MPH, an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at UCSF. “Although the data on drug resistance is very important to evaluate, we should certainly consider at this point using doxycycline PEP within 72 hours of condomless sex for our patients for STI prevention,” she said in an interview.

“In our practice, we are very excited about the possibility of a simple one-pill postexposure prophylactic agent (doxycycline 200 mg) to reduce the risk of a number of STIs. We have used PEP for HIV infection for a number of years and are very familiar with the concept of preventing infections after an exposure,” said Dr. Gandhi, director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “We are planning to institute doxycycline as PEP at my clinic after the release of these findings and will follow the remainder of the study findings closely.”

The trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, through grant R01AI143439. It was conducted at the HIV clinic at Zuckerberg San Francisco General Hospital and the San Francisco City Clinic, both part of the San Francisco Department of Public Health, and the Madison Clinic and the Sexual Health Clinic at Harborview Medical Center, both at the University of Washington. Medications were provided by Mayne Pharmaceuticals, and lab support by Hologic & Cepheid.

Dr. Lewin has the following disclosures: investigator-initiated, industry-funded research for Gilead, Viiv, Merck; scientific advisory board (honoraria paid to her personally) for Gilead, Merck, Viiv, Esfam, Immunocore, Vaxxinity; collaborative research (nonfunded) for AbbVie, Genentech, BMS. Dr. Luetkemeyer and Dr. Gandhi reported no relevant financial relationships.

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

MONTREAL – The case of a patient in an HIV study whose viral load dropped to undetectable levels and whose immune cells soared has captured the attention of organizers at a meeting of the International AIDS Society.

Although the 59-year-old woman is one of many who are known as posttreatment controllers (PTCs) – having been in remission for more than 15 years after stopping antiretroviral therapy (ART) – it is an immune-based therapy study in which she took part in 2005, and her unusually high levels of memory-like NK cells and gamma-delta T cells since then, that are raising some eyebrows.

“This case opens new avenues in the HIV functional-cure field,” lead investigator Núria Climent, PhD, of the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.

“As far as we know, this is the first time that the gamma-delta T cells have been identified in a PTC, and concerning the memory-like NK cells, there are very few published data and only sparse information presented in several congresses,” she said, explaining that these cells “have a high capacity to inhibit the replication of the virus in vitro. For that reason, we think that this PTC has cells able to dramatically reduce the virus amount. We think that the potential capacity to increase these cells in this PTC woman could be not only mediated by especial genetic factors ... but also mediated by early ART treatment and might be by the immunomediated treatment.”

The findings suggest the potential for “increasing the amount of those memory-like NK cells and gamma-delta T cells in order to translate this potent antiviral activity in new therapies to achieve an HIV functional cure,” she said, adding: “As far as we know, aiming to increase these specific cells has never been done before in people living with HIV.”

In a press conference during the meeting, Dr. Climent explained that the patient was enrolled in a study in which she received a combination of ART and immunomodulatory therapy. This involved a combination of cyclosporine A, low-dose interleukin 2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa-2b.

“None of the other 19 patients included in the trial controlled viral replication,” senior investigator Jose Miro, MD, PhD, also from the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.

Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the conference, said in an interview that although the significance of the case is unclear, the IAS selected it as a highlight for the meeting. “It is important for clinicians to understand the complexities in interpreting these case reports. Their patients are probably likely to ask them about the report, and it’s important [that] they can explain it to them.”

Dr. Lewin, who is professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity in Melbourne, added that it is impossible to determine the mechanism of action from a single case report. “We don’t know if the intervention played a role or if this person is a ‘posttreatment controller,’ which has been previously described many times,” she said in an interview. “In this patient, the virus is at very low, but controlled, levels, and virus could be grown out. While it’s still exciting and important, this is really what we would consider a remission. The intense study of a single case such as this is certainly worthwhile and important but can only provide new ideas for research. So, I don’t think we can draw any conclusion on the role of NK cells, et cetera. We need much larger case series or controlled trials to reach any conclusion on the reasons for her remission.”

Dr. Climent disclosed no relevant financial conflicts of interest. Dr. Lewin has disclosed investigator-initiated industry-funded research (Gilead, ViiV, Merck), scientific advisory board honoraria paid to her personally (Gilead, Merck, ViiV, Esfam, Immunocore, Vaxxinity), and nonfunded collaborative research (AbbVie, Genentech, Bristol-Myers Squibb).

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

MONTREAL – The case of a patient in an HIV study whose viral load dropped to undetectable levels and whose immune cells soared has captured the attention of organizers at a meeting of the International AIDS Society.

Although the 59-year-old woman is one of many who are known as posttreatment controllers (PTCs) – having been in remission for more than 15 years after stopping antiretroviral therapy (ART) – it is an immune-based therapy study in which she took part in 2005, and her unusually high levels of memory-like NK cells and gamma-delta T cells since then, that are raising some eyebrows.

“This case opens new avenues in the HIV functional-cure field,” lead investigator Núria Climent, PhD, of the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.

“As far as we know, this is the first time that the gamma-delta T cells have been identified in a PTC, and concerning the memory-like NK cells, there are very few published data and only sparse information presented in several congresses,” she said, explaining that these cells “have a high capacity to inhibit the replication of the virus in vitro. For that reason, we think that this PTC has cells able to dramatically reduce the virus amount. We think that the potential capacity to increase these cells in this PTC woman could be not only mediated by especial genetic factors ... but also mediated by early ART treatment and might be by the immunomediated treatment.”

The findings suggest the potential for “increasing the amount of those memory-like NK cells and gamma-delta T cells in order to translate this potent antiviral activity in new therapies to achieve an HIV functional cure,” she said, adding: “As far as we know, aiming to increase these specific cells has never been done before in people living with HIV.”

In a press conference during the meeting, Dr. Climent explained that the patient was enrolled in a study in which she received a combination of ART and immunomodulatory therapy. This involved a combination of cyclosporine A, low-dose interleukin 2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa-2b.

“None of the other 19 patients included in the trial controlled viral replication,” senior investigator Jose Miro, MD, PhD, also from the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.

Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the conference, said in an interview that although the significance of the case is unclear, the IAS selected it as a highlight for the meeting. “It is important for clinicians to understand the complexities in interpreting these case reports. Their patients are probably likely to ask them about the report, and it’s important [that] they can explain it to them.”

Dr. Lewin, who is professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity in Melbourne, added that it is impossible to determine the mechanism of action from a single case report. “We don’t know if the intervention played a role or if this person is a ‘posttreatment controller,’ which has been previously described many times,” she said in an interview. “In this patient, the virus is at very low, but controlled, levels, and virus could be grown out. While it’s still exciting and important, this is really what we would consider a remission. The intense study of a single case such as this is certainly worthwhile and important but can only provide new ideas for research. So, I don’t think we can draw any conclusion on the role of NK cells, et cetera. We need much larger case series or controlled trials to reach any conclusion on the reasons for her remission.”

Dr. Climent disclosed no relevant financial conflicts of interest. Dr. Lewin has disclosed investigator-initiated industry-funded research (Gilead, ViiV, Merck), scientific advisory board honoraria paid to her personally (Gilead, Merck, ViiV, Esfam, Immunocore, Vaxxinity), and nonfunded collaborative research (AbbVie, Genentech, Bristol-Myers Squibb).

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

MONTREAL – The case of a patient in an HIV study whose viral load dropped to undetectable levels and whose immune cells soared has captured the attention of organizers at a meeting of the International AIDS Society.

Although the 59-year-old woman is one of many who are known as posttreatment controllers (PTCs) – having been in remission for more than 15 years after stopping antiretroviral therapy (ART) – it is an immune-based therapy study in which she took part in 2005, and her unusually high levels of memory-like NK cells and gamma-delta T cells since then, that are raising some eyebrows.

“This case opens new avenues in the HIV functional-cure field,” lead investigator Núria Climent, PhD, of the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.

“As far as we know, this is the first time that the gamma-delta T cells have been identified in a PTC, and concerning the memory-like NK cells, there are very few published data and only sparse information presented in several congresses,” she said, explaining that these cells “have a high capacity to inhibit the replication of the virus in vitro. For that reason, we think that this PTC has cells able to dramatically reduce the virus amount. We think that the potential capacity to increase these cells in this PTC woman could be not only mediated by especial genetic factors ... but also mediated by early ART treatment and might be by the immunomediated treatment.”

The findings suggest the potential for “increasing the amount of those memory-like NK cells and gamma-delta T cells in order to translate this potent antiviral activity in new therapies to achieve an HIV functional cure,” she said, adding: “As far as we know, aiming to increase these specific cells has never been done before in people living with HIV.”

In a press conference during the meeting, Dr. Climent explained that the patient was enrolled in a study in which she received a combination of ART and immunomodulatory therapy. This involved a combination of cyclosporine A, low-dose interleukin 2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa-2b.

“None of the other 19 patients included in the trial controlled viral replication,” senior investigator Jose Miro, MD, PhD, also from the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.

Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the conference, said in an interview that although the significance of the case is unclear, the IAS selected it as a highlight for the meeting. “It is important for clinicians to understand the complexities in interpreting these case reports. Their patients are probably likely to ask them about the report, and it’s important [that] they can explain it to them.”

Dr. Lewin, who is professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity in Melbourne, added that it is impossible to determine the mechanism of action from a single case report. “We don’t know if the intervention played a role or if this person is a ‘posttreatment controller,’ which has been previously described many times,” she said in an interview. “In this patient, the virus is at very low, but controlled, levels, and virus could be grown out. While it’s still exciting and important, this is really what we would consider a remission. The intense study of a single case such as this is certainly worthwhile and important but can only provide new ideas for research. So, I don’t think we can draw any conclusion on the role of NK cells, et cetera. We need much larger case series or controlled trials to reach any conclusion on the reasons for her remission.”

Dr. Climent disclosed no relevant financial conflicts of interest. Dr. Lewin has disclosed investigator-initiated industry-funded research (Gilead, ViiV, Merck), scientific advisory board honoraria paid to her personally (Gilead, Merck, ViiV, Esfam, Immunocore, Vaxxinity), and nonfunded collaborative research (AbbVie, Genentech, Bristol-Myers Squibb).

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

MONTREAL – A 66-year-old U.S. man has become the world’s fourth known HIV patient to show complete clearance of the virus after being treated for acute myelogenous leukemia with an allogeneic hematopoietic stem cell transplantation from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.

The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.

Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.

She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.

Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.

“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”

“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.

“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.

Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.

The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.

Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.

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

MONTREAL – A 66-year-old U.S. man has become the world’s fourth known HIV patient to show complete clearance of the virus after being treated for acute myelogenous leukemia with an allogeneic hematopoietic stem cell transplantation from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.

The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.

Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.

She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.

Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.

“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”

“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.

“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.

Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.

The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.

Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.

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

MONTREAL – A 66-year-old U.S. man has become the world’s fourth known HIV patient to show complete clearance of the virus after being treated for acute myelogenous leukemia with an allogeneic hematopoietic stem cell transplantation from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.

The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.

Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.

She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.

Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.

“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”

“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.

“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.

Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.

The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.

Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.

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

Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.

Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.

“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”

The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.

Dr. Grupp said that he is, at last, starting to use the “cure” word.

“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’

“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
 

First patient with ALL

Emily was the first patient with ALL to receive the novel treatment, and also the first child.

There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.

But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.

But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”

Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.

Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
 

The ‘magic formula’

CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.

Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.

“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.

Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.

“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
 

Cytokine storm

The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.

The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.

But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.

“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.

“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”

“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
 

On the fly

It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”

They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.

“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.

“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”

Emily woke up from a 14-day medically induced coma on her seventh birthday.

Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.

She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
 

Talking about ‘cure’

Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.

Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.

“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].

“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
 

Hearing whispers

Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.

As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”

Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.

Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
 

Enduring effect

The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.

“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”

While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.

“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.

“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”

As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.

Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.

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

Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.

Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.

“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”

The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.

Dr. Grupp said that he is, at last, starting to use the “cure” word.

“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’

“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
 

First patient with ALL

Emily was the first patient with ALL to receive the novel treatment, and also the first child.

There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.

But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.

But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”

Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.

Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
 

The ‘magic formula’

CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.

Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.

“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.

Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.

“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
 

Cytokine storm

The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.

The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.

But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.

“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.

“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”

“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
 

On the fly

It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”

They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.

“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.

“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”

Emily woke up from a 14-day medically induced coma on her seventh birthday.

Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.

She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
 

Talking about ‘cure’

Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.

Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.

“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].

“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
 

Hearing whispers

Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.

As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”

Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.

Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
 

Enduring effect

The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.

“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”

While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.

“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.

“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”

As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.

Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.

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

Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.

Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.

“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”

The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.

Dr. Grupp said that he is, at last, starting to use the “cure” word.

“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’

“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
 

First patient with ALL

Emily was the first patient with ALL to receive the novel treatment, and also the first child.

There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.

But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.

But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”

Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.

Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
 

The ‘magic formula’

CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.

Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.

“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.

Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.

“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
 

Cytokine storm

The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.

The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.

But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.

“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.

“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”

“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
 

On the fly

It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”

They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.

“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.

“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”

Emily woke up from a 14-day medically induced coma on her seventh birthday.

Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.

She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
 

Talking about ‘cure’

Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.

Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.

“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].

“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
 

Hearing whispers

Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.

As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”

Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.

Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
 

Enduring effect

The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.

“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”

While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.

“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.

“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”

As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.

Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.

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

An open-label extension of Biogen’s phase 3 VALOR study shows statistically significant benefits for the company’s novel antisense oligonucleotide (ASO), tofersen, in patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations.

The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.

“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”

Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
 

One-year VALOR study results

The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.

For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.

There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.

“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”

Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.

Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).

Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).

Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
 

The bigger picture

While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.

“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
 

What lies ahead?

Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug.  I would like to be able to offer it to them.  But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.

“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”

Dr. Miller added that these results “highlight how difficult ALS drug development still is.  Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”

The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.

An open-label extension of Biogen’s phase 3 VALOR study shows statistically significant benefits for the company’s novel antisense oligonucleotide (ASO), tofersen, in patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations.

The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.

“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”

Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
 

One-year VALOR study results

The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.

For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.

There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.

“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”

Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.

Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).

Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).

Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
 

The bigger picture

While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.

“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
 

What lies ahead?

Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug.  I would like to be able to offer it to them.  But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.

“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”

Dr. Miller added that these results “highlight how difficult ALS drug development still is.  Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”

The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.

An open-label extension of Biogen’s phase 3 VALOR study shows statistically significant benefits for the company’s novel antisense oligonucleotide (ASO), tofersen, in patients with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations.

The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.

“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”

Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
 

One-year VALOR study results

The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.

For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.

There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.

“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”

Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.

Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).

Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).

Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
 

The bigger picture

While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.

“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
 

What lies ahead?

Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug.  I would like to be able to offer it to them.  But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.

“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”

Dr. Miller added that these results “highlight how difficult ALS drug development still is.  Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”

The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.