Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

The COVID-19 pandemic is a worldwide tragedy. In the beginning there was a lack of testing, personal protective equipment, COVID tests, and support for health care workers and patients. As 2020 came to a close, the world was given a glimpse of hope with the development of a vaccine against the deadly virus. Many world citizens celebrated the scientific accomplishment and began to breathe a sigh of relief that there was an end in sight. However, the development and distribution of the COVID-19 vaccine revealed a new challenge, vaccine hesitancy.

Community members, young healthy people, and even critically ill hospitalized patients who have the fortune of surviving acute illness are hesitant to the COVID-19 vaccine. I recently cared for a critically ill young patient who was intubated for days with status asthmaticus, one of the worst cases I’d ever seen. She was extubated and made a full recovery. Prior to discharge I asked if she wanted the first dose of the COVID-19 vaccine and she said, “No.” I was shocked. This was an otherwise healthy 30-something-year-old who was lucky enough to survive without any underlying infection in the setting of severe obstructive lung disease. A co-infection with COVID-19 would be disastrous and increase her mortality. I had a long talk at the bedside and asked the reason for her hesitancy. Her answer left me speechless, “I don’t know, I just don’t want to.” I ultimately convinced her that contracting COVID-19 would be a fate worse than she could imagine, and she agreed to the vaccine prior to discharge. This interaction made me ponder – “why are our patients, friends, and family members hesitant about receiving a lifesaving vaccine, especially when they are aware of how sick they or others can become without it?”

According to the World Health Organization, vaccine hesitancy refers to a delay in acceptance or refusal of vaccines despite availability of vaccine services. Vaccine hesitancy is complex and context specific, varying across time, place, and vaccines. It is influenced by factors such as complacency, convenience, and confidence.¹ No vaccine is 100% effective. However, throughout history, the work of scientists and doctors to create vaccines saved millions of lives and revolutionized global health. Arguably, the single most life-saving innovation in the history of medicine, vaccines have eradicated smallpox, protected against whooping cough (1914), diphtheria (1926), tetanus (1938), influenza (1945) and mumps (1948), polio (1955), measles (1963), and rubella (1969), and worldwide vaccination rates increased dramatically thanks to successful global health campaigns.² However, there was a paradox of vaccine success. As terrifying diseases decreased in prevalence, so did the fear of these diseases and their effects – paralysis, brain damage, blindness, and death. This gave birth to a new challenge in modern medicine, vaccine hesitancy – a privilege of first world nations.

Vaccines saved countless lives and improved health and wellbeing around the world for decades. However, to prevent the morbidity and mortality associated with vaccine-preventable diseases and their complications, and optimize control of vaccine-preventable diseases in communities, high vaccination rates must be achieved. Enter the COVID-19 pandemic, the creation of the COVID-19 vaccine, and vaccine hesitancy.

The question we ask ourselves as health care providers is ‘how do we convince the skeptics and those opposed to vaccination to take the vaccine?’ The answer is complicated. If you are like me, you’ve had many conversations with people – friends, patients, family members, who are resistant to the vaccine. Very often the facts are not well received, and those discussions end in argument, high emotions, and broken relationships. With the delta variant of COVID-19 on the rise, spreading aggressively among the unvaccinated, and increased hospitalizations, we foresee the reoccurrence of overwhelmed health systems and a continued death toll.

The new paradox we are faced with is that people choose to believe fiction versus fact, despite the real life evidence of the severe health effects and increased deaths related to COVID-19. Do these skeptics simply have a cavalier attitude towards not only their own life, but the lives of others? Or, is there something deeper? It is not enough to tell people that the vaccines are proven safe³ and are more widely available than ever. It is not enough to tell people that they can die of COVID-19 – they already know that. Emotional pleas to family members are falling on deaf ears. This past month, when asking patients why they don’t want the vaccine, many have no real legitimate health-related reason and respond with a simple, “I don’t want to.” So, how do we get through to the unvaccinated?
 

A compassionate approach

We navigate these difficult conversations over time with the approach of compassion and empathy, not hostility or bullying. As health care providers, we start by being good empathic listeners. Similar to when we have advance care planning and code status conversations, we cannot enter the dialogue with our intention, beliefs, or formulated goals for that person. We have to listen without judgement to the wide range of reasons why others are reluctant or unwilling to get the vaccine – historical mistrust, political identity, religious reasons, short-term side effects that may cause them to lose a day or two of work – and understand that for each person their reasons are different. The point is to not assume that you know or understand what barriers and beliefs they have towards vaccination, but to meet them at their point of view and listen while keeping your own emotions level and steady.

Identifying the reason for vaccine hesitancy is the first step to getting the unvaccinated closer to vaccination. Ask open ended questions: “Can you help me understand, what is your hesitancy to the vaccine?”; “What about the vaccine worries you?”; “What have you heard about/know about the COVID-19 vaccine?”; or “Can you tell me more about why you feel that way?” As meticulous as it sounds, we have to go back to the basics of patient interviewing.

It is important to remember that this is not a debate and escalation to arguments will certainly backfire. Think about any time you disagreed with someone on a topic. Did criticizing, blaming, and shaming ever convince you to change your beliefs or behaviors? The likely answer is, “No.” Avoid the “backfire effect”– which is when giving people facts disproving their “incorrect” beliefs can actually reinforce those beliefs. The more people are confronted with facts at odds with their opinions, the stronger they cling to those opinions. If you want them to change their mind, you cannot approach the conversation as a debate. You are having this vaccine discussion to try to meet the other person where they are, understand their position, and talk with them, and not at them, about their concerns.

As leaders in health care, we have to be willing to give up control and lead with empathy. We have to show others that we hear them, believe their concerns, and acknowledge that their beliefs are valid to them as individuals. Even if you disagree, this is not the place to let anger, disappointment, or resentment take a front seat. This is about balance, and highlighting the autonomy in decision making that the other person has to make a choice. Be humble in these conversations and avoid condescending tones or statements.

We already know that you are a caring health care provider. As hospitalists, we are frontline providers who have seen unnecessary deaths and illness due to COVID-19. You are passionate and motivated because you are committed to your oath to save lives. However, you have to check your own feelings and remember that you are not speaking with an unvaccinated person to make them get vaccinated, but rather to understand their cognitive process and hopefully walk with them down a path that provides them with a clarity of options they truly have. Extend empathy and they will see your motivation is rooted in good-heartedness and a concern for their wellbeing.

If someone admits to reasons for avoiding vaccination that are not rooted in any fact, then guide them to the best resources. Our health care system recently released a COVID-19 fact versus myth handout called Trust the Facts. This could be the kind of vetted resource you offer. Guide them to accredited websites, such as the World Health Organization, the Center for Disease Control, or their local and state departments of health to help debunk fiction by reviewing it with them. Discuss myths such as, ‘the vaccine will cause infertility,’ ‘the vaccine will give me COVID,’ ‘the vaccine was rushed and is not safe,’ ‘the vaccine is not needed if I am young and healthy,’ ‘the vaccine has a microchip,’ etc. Knowledge is power and disinformation is deadly, but how facts are presented will make the biggest difference in how others receive them, so remember your role is not to argue with these statements, but rather to provide perspective without agreeing or disagreeing.

Respond to their concerns with statements such as, “I hear you…it sounds like you are worried/fearful/mistrusting about the side effects/safety/efficacy of the vaccine…can we talk more about that?” Ask them where these concerns come from – the news, social media, an article, word of mouth, friends, or family. Ask them about the information they have and show genuine interest that you want to see it from their perspective. This is the key to compassionate and empathic dialogue – you relinquish your intentions.

Once you know or unveil their reasons for hesitancy, ask them what they would like to see with regards to COVID-19 and ending the pandemic. Would they like to get back to a new normal, to visit family members, to travel once again, to not have to wear masks and quarantine? What do they want for themselves, their families, communities, the country, or even the world? The goal is to find something in our shared humanity, to connect on a deeper level so they start to open up and let down walls, and find something you both see eye-to-eye on. Know your audience and speak to what serves them. To effectively persuade someone to come around to your point of view starts with recognizing the root of the disagreement and trying to overcome it before trying to change the person’s mind, understanding both the logic and the emotion that’s driving their decision making.⁴
 

Building trust

Reminding patients, friends or family members that their health and well-being means a lot to you can also be a strategy to keeping the conversation open and friendly. Sharing stories as hospitalists caring for many critically ill COVID patients or patients who died alone due to COVID-19, and the trauma you experienced as a health care provider feeling paralyzed by the limitations of modern medicine against the deadly virus, will only serve to humanize you in such an interaction.

Building trust will also increase vaccine willingness. This will require a concerted effort by scientists, doctors, and health care systems to engage with community leaders and members. To address hesitancy, the people we serve have to hear those local, personal, and relatable stories about vaccinations, and how it benefits not just themselves, but others around them in their community. As part of the #VaxUp campaign in Virginia, community and physician leaders shared their stories of hesitancy and motivation surrounding the vaccine. These are real people in the community discussing why getting vaccinated is so important and what helped them make an informed decision. I discussed my own hesitancy and concerns and also tackled a few vaccine myths.

As vaccinated health care workers or community leaders, you are living proof of the benefits of getting the COVID vaccine. Focus on the positives but also be honest. If your second shot gave you fevers, chills, or myalgias, then admit it and share how you overcame these expected reactions. Refocus on the safety of the vaccine and the fact that it is freely available to all people. Maybe the person you are speaking with doesn’t know where or how to get an appointment to get vaccinated. Help them find the nearest place to get an appointment and identify barriers they may have in transportation, child, or senior care to leave home safely to get vaccinated, or physical conditions that are preventing them from receiving the vaccine. Share that being vaccinated protects you from contracting the virus and spreading it to loved ones. Focus on how a fully vaccinated community and country can open up opportunities to heal and connect as a society, spend time with family/friends in another county or state, hold a newborn grandchild, or even travel outside the U.S.

There is no guarantee that you will be able to persuade someone to get vaccinated. It’s possible the outcome of your conversation will not result in the other person changing their mind in that moment. That doesn’t mean that you failed, because you started the dialogue and planted the seed. If you are a vaccinated health care provider, your words have influence and power, and we are obliged by our positions to have responsibility for the health of our communities. Don’t be discouraged, as it is through caring, compassionate, respectful, and empathic conversations that your influence will make the most difference in these relationships as you continue to advocate for all human life.
 

Dr. Williams is vice president of the Hampton Roads chapter of the Society of Hospital Medicine. She is a hospitalist at Sentara Careplex Hospital in Hampton, Va., where she also serves as vice president of the Medical Executive Committee.

References

1. World Health Organization. Report of the SAGE working group on vaccine hesitancy. Oct 2014. https://www.who.int/immunization/sage/meetings/2014/october/1_Report_WORKING_GROUP_vaccine_hesitancy_final.pdf

2. Hsu JL. A brief history of vaccines: Smallpox to the present. S D Med. 2013;Spec no:33-7. PMID: 23444589.

3. Chiu A, Bever L. Are they experimental? Can they alter DNA? Experts tackle lingering coronavirus vaccine fears. The Washington Post. 2021 May 14. https://www.washingtonpost.com/lifestyle/2021/05/14/safe-fast-vaccine-fear-infertility-dna/

4. Huang L. Edge: Turning Adversity into Advantage. New York: Portfolio/Penguin, 2020.

The COVID-19 pandemic is a worldwide tragedy. In the beginning there was a lack of testing, personal protective equipment, COVID tests, and support for health care workers and patients. As 2020 came to a close, the world was given a glimpse of hope with the development of a vaccine against the deadly virus. Many world citizens celebrated the scientific accomplishment and began to breathe a sigh of relief that there was an end in sight. However, the development and distribution of the COVID-19 vaccine revealed a new challenge, vaccine hesitancy.

Community members, young healthy people, and even critically ill hospitalized patients who have the fortune of surviving acute illness are hesitant to the COVID-19 vaccine. I recently cared for a critically ill young patient who was intubated for days with status asthmaticus, one of the worst cases I’d ever seen. She was extubated and made a full recovery. Prior to discharge I asked if she wanted the first dose of the COVID-19 vaccine and she said, “No.” I was shocked. This was an otherwise healthy 30-something-year-old who was lucky enough to survive without any underlying infection in the setting of severe obstructive lung disease. A co-infection with COVID-19 would be disastrous and increase her mortality. I had a long talk at the bedside and asked the reason for her hesitancy. Her answer left me speechless, “I don’t know, I just don’t want to.” I ultimately convinced her that contracting COVID-19 would be a fate worse than she could imagine, and she agreed to the vaccine prior to discharge. This interaction made me ponder – “why are our patients, friends, and family members hesitant about receiving a lifesaving vaccine, especially when they are aware of how sick they or others can become without it?”

According to the World Health Organization, vaccine hesitancy refers to a delay in acceptance or refusal of vaccines despite availability of vaccine services. Vaccine hesitancy is complex and context specific, varying across time, place, and vaccines. It is influenced by factors such as complacency, convenience, and confidence.¹ No vaccine is 100% effective. However, throughout history, the work of scientists and doctors to create vaccines saved millions of lives and revolutionized global health. Arguably, the single most life-saving innovation in the history of medicine, vaccines have eradicated smallpox, protected against whooping cough (1914), diphtheria (1926), tetanus (1938), influenza (1945) and mumps (1948), polio (1955), measles (1963), and rubella (1969), and worldwide vaccination rates increased dramatically thanks to successful global health campaigns.² However, there was a paradox of vaccine success. As terrifying diseases decreased in prevalence, so did the fear of these diseases and their effects – paralysis, brain damage, blindness, and death. This gave birth to a new challenge in modern medicine, vaccine hesitancy – a privilege of first world nations.

Vaccines saved countless lives and improved health and wellbeing around the world for decades. However, to prevent the morbidity and mortality associated with vaccine-preventable diseases and their complications, and optimize control of vaccine-preventable diseases in communities, high vaccination rates must be achieved. Enter the COVID-19 pandemic, the creation of the COVID-19 vaccine, and vaccine hesitancy.

The question we ask ourselves as health care providers is ‘how do we convince the skeptics and those opposed to vaccination to take the vaccine?’ The answer is complicated. If you are like me, you’ve had many conversations with people – friends, patients, family members, who are resistant to the vaccine. Very often the facts are not well received, and those discussions end in argument, high emotions, and broken relationships. With the delta variant of COVID-19 on the rise, spreading aggressively among the unvaccinated, and increased hospitalizations, we foresee the reoccurrence of overwhelmed health systems and a continued death toll.

The new paradox we are faced with is that people choose to believe fiction versus fact, despite the real life evidence of the severe health effects and increased deaths related to COVID-19. Do these skeptics simply have a cavalier attitude towards not only their own life, but the lives of others? Or, is there something deeper? It is not enough to tell people that the vaccines are proven safe³ and are more widely available than ever. It is not enough to tell people that they can die of COVID-19 – they already know that. Emotional pleas to family members are falling on deaf ears. This past month, when asking patients why they don’t want the vaccine, many have no real legitimate health-related reason and respond with a simple, “I don’t want to.” So, how do we get through to the unvaccinated?
 

A compassionate approach

We navigate these difficult conversations over time with the approach of compassion and empathy, not hostility or bullying. As health care providers, we start by being good empathic listeners. Similar to when we have advance care planning and code status conversations, we cannot enter the dialogue with our intention, beliefs, or formulated goals for that person. We have to listen without judgement to the wide range of reasons why others are reluctant or unwilling to get the vaccine – historical mistrust, political identity, religious reasons, short-term side effects that may cause them to lose a day or two of work – and understand that for each person their reasons are different. The point is to not assume that you know or understand what barriers and beliefs they have towards vaccination, but to meet them at their point of view and listen while keeping your own emotions level and steady.

Identifying the reason for vaccine hesitancy is the first step to getting the unvaccinated closer to vaccination. Ask open ended questions: “Can you help me understand, what is your hesitancy to the vaccine?”; “What about the vaccine worries you?”; “What have you heard about/know about the COVID-19 vaccine?”; or “Can you tell me more about why you feel that way?” As meticulous as it sounds, we have to go back to the basics of patient interviewing.

It is important to remember that this is not a debate and escalation to arguments will certainly backfire. Think about any time you disagreed with someone on a topic. Did criticizing, blaming, and shaming ever convince you to change your beliefs or behaviors? The likely answer is, “No.” Avoid the “backfire effect”– which is when giving people facts disproving their “incorrect” beliefs can actually reinforce those beliefs. The more people are confronted with facts at odds with their opinions, the stronger they cling to those opinions. If you want them to change their mind, you cannot approach the conversation as a debate. You are having this vaccine discussion to try to meet the other person where they are, understand their position, and talk with them, and not at them, about their concerns.

As leaders in health care, we have to be willing to give up control and lead with empathy. We have to show others that we hear them, believe their concerns, and acknowledge that their beliefs are valid to them as individuals. Even if you disagree, this is not the place to let anger, disappointment, or resentment take a front seat. This is about balance, and highlighting the autonomy in decision making that the other person has to make a choice. Be humble in these conversations and avoid condescending tones or statements.

We already know that you are a caring health care provider. As hospitalists, we are frontline providers who have seen unnecessary deaths and illness due to COVID-19. You are passionate and motivated because you are committed to your oath to save lives. However, you have to check your own feelings and remember that you are not speaking with an unvaccinated person to make them get vaccinated, but rather to understand their cognitive process and hopefully walk with them down a path that provides them with a clarity of options they truly have. Extend empathy and they will see your motivation is rooted in good-heartedness and a concern for their wellbeing.

If someone admits to reasons for avoiding vaccination that are not rooted in any fact, then guide them to the best resources. Our health care system recently released a COVID-19 fact versus myth handout called Trust the Facts. This could be the kind of vetted resource you offer. Guide them to accredited websites, such as the World Health Organization, the Center for Disease Control, or their local and state departments of health to help debunk fiction by reviewing it with them. Discuss myths such as, ‘the vaccine will cause infertility,’ ‘the vaccine will give me COVID,’ ‘the vaccine was rushed and is not safe,’ ‘the vaccine is not needed if I am young and healthy,’ ‘the vaccine has a microchip,’ etc. Knowledge is power and disinformation is deadly, but how facts are presented will make the biggest difference in how others receive them, so remember your role is not to argue with these statements, but rather to provide perspective without agreeing or disagreeing.

Respond to their concerns with statements such as, “I hear you…it sounds like you are worried/fearful/mistrusting about the side effects/safety/efficacy of the vaccine…can we talk more about that?” Ask them where these concerns come from – the news, social media, an article, word of mouth, friends, or family. Ask them about the information they have and show genuine interest that you want to see it from their perspective. This is the key to compassionate and empathic dialogue – you relinquish your intentions.

Once you know or unveil their reasons for hesitancy, ask them what they would like to see with regards to COVID-19 and ending the pandemic. Would they like to get back to a new normal, to visit family members, to travel once again, to not have to wear masks and quarantine? What do they want for themselves, their families, communities, the country, or even the world? The goal is to find something in our shared humanity, to connect on a deeper level so they start to open up and let down walls, and find something you both see eye-to-eye on. Know your audience and speak to what serves them. To effectively persuade someone to come around to your point of view starts with recognizing the root of the disagreement and trying to overcome it before trying to change the person’s mind, understanding both the logic and the emotion that’s driving their decision making.⁴
 

Building trust

Reminding patients, friends or family members that their health and well-being means a lot to you can also be a strategy to keeping the conversation open and friendly. Sharing stories as hospitalists caring for many critically ill COVID patients or patients who died alone due to COVID-19, and the trauma you experienced as a health care provider feeling paralyzed by the limitations of modern medicine against the deadly virus, will only serve to humanize you in such an interaction.

Building trust will also increase vaccine willingness. This will require a concerted effort by scientists, doctors, and health care systems to engage with community leaders and members. To address hesitancy, the people we serve have to hear those local, personal, and relatable stories about vaccinations, and how it benefits not just themselves, but others around them in their community. As part of the #VaxUp campaign in Virginia, community and physician leaders shared their stories of hesitancy and motivation surrounding the vaccine. These are real people in the community discussing why getting vaccinated is so important and what helped them make an informed decision. I discussed my own hesitancy and concerns and also tackled a few vaccine myths.

As vaccinated health care workers or community leaders, you are living proof of the benefits of getting the COVID vaccine. Focus on the positives but also be honest. If your second shot gave you fevers, chills, or myalgias, then admit it and share how you overcame these expected reactions. Refocus on the safety of the vaccine and the fact that it is freely available to all people. Maybe the person you are speaking with doesn’t know where or how to get an appointment to get vaccinated. Help them find the nearest place to get an appointment and identify barriers they may have in transportation, child, or senior care to leave home safely to get vaccinated, or physical conditions that are preventing them from receiving the vaccine. Share that being vaccinated protects you from contracting the virus and spreading it to loved ones. Focus on how a fully vaccinated community and country can open up opportunities to heal and connect as a society, spend time with family/friends in another county or state, hold a newborn grandchild, or even travel outside the U.S.

There is no guarantee that you will be able to persuade someone to get vaccinated. It’s possible the outcome of your conversation will not result in the other person changing their mind in that moment. That doesn’t mean that you failed, because you started the dialogue and planted the seed. If you are a vaccinated health care provider, your words have influence and power, and we are obliged by our positions to have responsibility for the health of our communities. Don’t be discouraged, as it is through caring, compassionate, respectful, and empathic conversations that your influence will make the most difference in these relationships as you continue to advocate for all human life.
 

Dr. Williams is vice president of the Hampton Roads chapter of the Society of Hospital Medicine. She is a hospitalist at Sentara Careplex Hospital in Hampton, Va., where she also serves as vice president of the Medical Executive Committee.

References

1. World Health Organization. Report of the SAGE working group on vaccine hesitancy. Oct 2014. https://www.who.int/immunization/sage/meetings/2014/october/1_Report_WORKING_GROUP_vaccine_hesitancy_final.pdf

2. Hsu JL. A brief history of vaccines: Smallpox to the present. S D Med. 2013;Spec no:33-7. PMID: 23444589.

3. Chiu A, Bever L. Are they experimental? Can they alter DNA? Experts tackle lingering coronavirus vaccine fears. The Washington Post. 2021 May 14. https://www.washingtonpost.com/lifestyle/2021/05/14/safe-fast-vaccine-fear-infertility-dna/

4. Huang L. Edge: Turning Adversity into Advantage. New York: Portfolio/Penguin, 2020.

The COVID-19 pandemic is a worldwide tragedy. In the beginning there was a lack of testing, personal protective equipment, COVID tests, and support for health care workers and patients. As 2020 came to a close, the world was given a glimpse of hope with the development of a vaccine against the deadly virus. Many world citizens celebrated the scientific accomplishment and began to breathe a sigh of relief that there was an end in sight. However, the development and distribution of the COVID-19 vaccine revealed a new challenge, vaccine hesitancy.

Community members, young healthy people, and even critically ill hospitalized patients who have the fortune of surviving acute illness are hesitant to the COVID-19 vaccine. I recently cared for a critically ill young patient who was intubated for days with status asthmaticus, one of the worst cases I’d ever seen. She was extubated and made a full recovery. Prior to discharge I asked if she wanted the first dose of the COVID-19 vaccine and she said, “No.” I was shocked. This was an otherwise healthy 30-something-year-old who was lucky enough to survive without any underlying infection in the setting of severe obstructive lung disease. A co-infection with COVID-19 would be disastrous and increase her mortality. I had a long talk at the bedside and asked the reason for her hesitancy. Her answer left me speechless, “I don’t know, I just don’t want to.” I ultimately convinced her that contracting COVID-19 would be a fate worse than she could imagine, and she agreed to the vaccine prior to discharge. This interaction made me ponder – “why are our patients, friends, and family members hesitant about receiving a lifesaving vaccine, especially when they are aware of how sick they or others can become without it?”

According to the World Health Organization, vaccine hesitancy refers to a delay in acceptance or refusal of vaccines despite availability of vaccine services. Vaccine hesitancy is complex and context specific, varying across time, place, and vaccines. It is influenced by factors such as complacency, convenience, and confidence.¹ No vaccine is 100% effective. However, throughout history, the work of scientists and doctors to create vaccines saved millions of lives and revolutionized global health. Arguably, the single most life-saving innovation in the history of medicine, vaccines have eradicated smallpox, protected against whooping cough (1914), diphtheria (1926), tetanus (1938), influenza (1945) and mumps (1948), polio (1955), measles (1963), and rubella (1969), and worldwide vaccination rates increased dramatically thanks to successful global health campaigns.² However, there was a paradox of vaccine success. As terrifying diseases decreased in prevalence, so did the fear of these diseases and their effects – paralysis, brain damage, blindness, and death. This gave birth to a new challenge in modern medicine, vaccine hesitancy – a privilege of first world nations.

Vaccines saved countless lives and improved health and wellbeing around the world for decades. However, to prevent the morbidity and mortality associated with vaccine-preventable diseases and their complications, and optimize control of vaccine-preventable diseases in communities, high vaccination rates must be achieved. Enter the COVID-19 pandemic, the creation of the COVID-19 vaccine, and vaccine hesitancy.

The question we ask ourselves as health care providers is ‘how do we convince the skeptics and those opposed to vaccination to take the vaccine?’ The answer is complicated. If you are like me, you’ve had many conversations with people – friends, patients, family members, who are resistant to the vaccine. Very often the facts are not well received, and those discussions end in argument, high emotions, and broken relationships. With the delta variant of COVID-19 on the rise, spreading aggressively among the unvaccinated, and increased hospitalizations, we foresee the reoccurrence of overwhelmed health systems and a continued death toll.

The new paradox we are faced with is that people choose to believe fiction versus fact, despite the real life evidence of the severe health effects and increased deaths related to COVID-19. Do these skeptics simply have a cavalier attitude towards not only their own life, but the lives of others? Or, is there something deeper? It is not enough to tell people that the vaccines are proven safe³ and are more widely available than ever. It is not enough to tell people that they can die of COVID-19 – they already know that. Emotional pleas to family members are falling on deaf ears. This past month, when asking patients why they don’t want the vaccine, many have no real legitimate health-related reason and respond with a simple, “I don’t want to.” So, how do we get through to the unvaccinated?
 

A compassionate approach

We navigate these difficult conversations over time with the approach of compassion and empathy, not hostility or bullying. As health care providers, we start by being good empathic listeners. Similar to when we have advance care planning and code status conversations, we cannot enter the dialogue with our intention, beliefs, or formulated goals for that person. We have to listen without judgement to the wide range of reasons why others are reluctant or unwilling to get the vaccine – historical mistrust, political identity, religious reasons, short-term side effects that may cause them to lose a day or two of work – and understand that for each person their reasons are different. The point is to not assume that you know or understand what barriers and beliefs they have towards vaccination, but to meet them at their point of view and listen while keeping your own emotions level and steady.

Identifying the reason for vaccine hesitancy is the first step to getting the unvaccinated closer to vaccination. Ask open ended questions: “Can you help me understand, what is your hesitancy to the vaccine?”; “What about the vaccine worries you?”; “What have you heard about/know about the COVID-19 vaccine?”; or “Can you tell me more about why you feel that way?” As meticulous as it sounds, we have to go back to the basics of patient interviewing.

It is important to remember that this is not a debate and escalation to arguments will certainly backfire. Think about any time you disagreed with someone on a topic. Did criticizing, blaming, and shaming ever convince you to change your beliefs or behaviors? The likely answer is, “No.” Avoid the “backfire effect”– which is when giving people facts disproving their “incorrect” beliefs can actually reinforce those beliefs. The more people are confronted with facts at odds with their opinions, the stronger they cling to those opinions. If you want them to change their mind, you cannot approach the conversation as a debate. You are having this vaccine discussion to try to meet the other person where they are, understand their position, and talk with them, and not at them, about their concerns.

As leaders in health care, we have to be willing to give up control and lead with empathy. We have to show others that we hear them, believe their concerns, and acknowledge that their beliefs are valid to them as individuals. Even if you disagree, this is not the place to let anger, disappointment, or resentment take a front seat. This is about balance, and highlighting the autonomy in decision making that the other person has to make a choice. Be humble in these conversations and avoid condescending tones or statements.

We already know that you are a caring health care provider. As hospitalists, we are frontline providers who have seen unnecessary deaths and illness due to COVID-19. You are passionate and motivated because you are committed to your oath to save lives. However, you have to check your own feelings and remember that you are not speaking with an unvaccinated person to make them get vaccinated, but rather to understand their cognitive process and hopefully walk with them down a path that provides them with a clarity of options they truly have. Extend empathy and they will see your motivation is rooted in good-heartedness and a concern for their wellbeing.

If someone admits to reasons for avoiding vaccination that are not rooted in any fact, then guide them to the best resources. Our health care system recently released a COVID-19 fact versus myth handout called Trust the Facts. This could be the kind of vetted resource you offer. Guide them to accredited websites, such as the World Health Organization, the Center for Disease Control, or their local and state departments of health to help debunk fiction by reviewing it with them. Discuss myths such as, ‘the vaccine will cause infertility,’ ‘the vaccine will give me COVID,’ ‘the vaccine was rushed and is not safe,’ ‘the vaccine is not needed if I am young and healthy,’ ‘the vaccine has a microchip,’ etc. Knowledge is power and disinformation is deadly, but how facts are presented will make the biggest difference in how others receive them, so remember your role is not to argue with these statements, but rather to provide perspective without agreeing or disagreeing.

Respond to their concerns with statements such as, “I hear you…it sounds like you are worried/fearful/mistrusting about the side effects/safety/efficacy of the vaccine…can we talk more about that?” Ask them where these concerns come from – the news, social media, an article, word of mouth, friends, or family. Ask them about the information they have and show genuine interest that you want to see it from their perspective. This is the key to compassionate and empathic dialogue – you relinquish your intentions.

Once you know or unveil their reasons for hesitancy, ask them what they would like to see with regards to COVID-19 and ending the pandemic. Would they like to get back to a new normal, to visit family members, to travel once again, to not have to wear masks and quarantine? What do they want for themselves, their families, communities, the country, or even the world? The goal is to find something in our shared humanity, to connect on a deeper level so they start to open up and let down walls, and find something you both see eye-to-eye on. Know your audience and speak to what serves them. To effectively persuade someone to come around to your point of view starts with recognizing the root of the disagreement and trying to overcome it before trying to change the person’s mind, understanding both the logic and the emotion that’s driving their decision making.⁴
 

Building trust

Reminding patients, friends or family members that their health and well-being means a lot to you can also be a strategy to keeping the conversation open and friendly. Sharing stories as hospitalists caring for many critically ill COVID patients or patients who died alone due to COVID-19, and the trauma you experienced as a health care provider feeling paralyzed by the limitations of modern medicine against the deadly virus, will only serve to humanize you in such an interaction.

Building trust will also increase vaccine willingness. This will require a concerted effort by scientists, doctors, and health care systems to engage with community leaders and members. To address hesitancy, the people we serve have to hear those local, personal, and relatable stories about vaccinations, and how it benefits not just themselves, but others around them in their community. As part of the #VaxUp campaign in Virginia, community and physician leaders shared their stories of hesitancy and motivation surrounding the vaccine. These are real people in the community discussing why getting vaccinated is so important and what helped them make an informed decision. I discussed my own hesitancy and concerns and also tackled a few vaccine myths.

As vaccinated health care workers or community leaders, you are living proof of the benefits of getting the COVID vaccine. Focus on the positives but also be honest. If your second shot gave you fevers, chills, or myalgias, then admit it and share how you overcame these expected reactions. Refocus on the safety of the vaccine and the fact that it is freely available to all people. Maybe the person you are speaking with doesn’t know where or how to get an appointment to get vaccinated. Help them find the nearest place to get an appointment and identify barriers they may have in transportation, child, or senior care to leave home safely to get vaccinated, or physical conditions that are preventing them from receiving the vaccine. Share that being vaccinated protects you from contracting the virus and spreading it to loved ones. Focus on how a fully vaccinated community and country can open up opportunities to heal and connect as a society, spend time with family/friends in another county or state, hold a newborn grandchild, or even travel outside the U.S.

There is no guarantee that you will be able to persuade someone to get vaccinated. It’s possible the outcome of your conversation will not result in the other person changing their mind in that moment. That doesn’t mean that you failed, because you started the dialogue and planted the seed. If you are a vaccinated health care provider, your words have influence and power, and we are obliged by our positions to have responsibility for the health of our communities. Don’t be discouraged, as it is through caring, compassionate, respectful, and empathic conversations that your influence will make the most difference in these relationships as you continue to advocate for all human life.
 

Dr. Williams is vice president of the Hampton Roads chapter of the Society of Hospital Medicine. She is a hospitalist at Sentara Careplex Hospital in Hampton, Va., where she also serves as vice president of the Medical Executive Committee.

References

1. World Health Organization. Report of the SAGE working group on vaccine hesitancy. Oct 2014. https://www.who.int/immunization/sage/meetings/2014/october/1_Report_WORKING_GROUP_vaccine_hesitancy_final.pdf

2. Hsu JL. A brief history of vaccines: Smallpox to the present. S D Med. 2013;Spec no:33-7. PMID: 23444589.

3. Chiu A, Bever L. Are they experimental? Can they alter DNA? Experts tackle lingering coronavirus vaccine fears. The Washington Post. 2021 May 14. https://www.washingtonpost.com/lifestyle/2021/05/14/safe-fast-vaccine-fear-infertility-dna/

4. Huang L. Edge: Turning Adversity into Advantage. New York: Portfolio/Penguin, 2020.

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

Nearly 80% of men with metastatic prostate cancer died from their malignancy, according to a retrospective cohort study involving 26,000-plus American men diagnosed with advanced disease in roughly the last 20 years.

The findings fill an information gap because, remarkably, “data are lacking” on causes of death among men whose prostate cancer has spread to other sites, say lead author Ahmed Elmehrath, MD, of Cairo University, Egypt, and colleagues.

“It was an important realization by our team that prostate cancer was the cause of death in 78% of patients,” said senior author Omar Alhalabi, MD, of University of Texas MD Anderson Cancer Center, Houston, in an email.

“Most patients with metastatic prostate cancer die from it, rather than other possible causes of death,” confirm Samuel Merriel, MSc, Tanimola Martins, PhD, and Sarah Bailey, PhD, University of Exeter, United Kingdom, in an accompanying editorial. The study was published last month in JAMA Network Open.

The findings represent the near opposite of a commonly held – and comforting – belief about early-stage disease: “You die with prostate cancer, not from it.”

That old saying is articulated in various ways, such as this from the Prostate Cancer Foundation: “We can confirm that there are those prostate cancers a man may die with and not of, while others are very aggressive.” The American Cancer Society says this: “Prostate cancer can be a serious disease, but most men diagnosed with prostate cancer do not die from it.”

However, these commonplace comments do not cover metastatic disease, which is what the authors of the new study decided to focus on.  

The team used data from the Surveillance, Epidemiology, and End Results Program (SEER) database to gather a sample of 26,168 U.S. men who received a diagnosis of metastatic prostate cancer from January 2000 to December 2016. They then analyzed the data in 2020 and found that 16,732 men (64%) had died during the follow-up period.

The majority of these deaths (77.8%) were from prostate cancer, 5.5% were from other cancers, and 16.7% were from noncancer causes, including cardiovascular diseases, chronic obstructive pulmonary disease, and cerebrovascular diseases.

Senior author Dr. Alhalabi acknowledged a limitation in these findings – that the SEER database relies on causes of death extracted from death certificates. “Death certificates have limited granularity in terms of the details they can contain about the cause of death and also have reporting bias,” he said.

Most of the prostate cancer deaths (59%) occurred within 2 years. The 5-year overall survival rate in the study group was 26%.

The deadliness of metastatic disease “reinforces the need for innovations to promote early-stage diagnosis,” comment the editorialists. Striking a hopeful note, they also say that “new tests for prostate cancer detection may reduce the proportion of patients who receive a diagnosis at a late stage.”
 

Death from other causes

The mean age at metastatic prostate cancer diagnosis in the study was roughly 71 years. Most of the cohort was White (74.5%) and had a diagnosis of stage M1b metastatic prostate cancer (72.7%), which means the cancer had spread to the bones.

Among men in the cohort, the rates of death from septicemia, suicide, accidents, COPD, and cerebrovascular diseases were significantly increased compared with the general U.S. male population, the team observes.

Thus, the study authors were concerned with not only with death from metastatic prostate cancer but death from other causes.

That concern is rooted in the established fact that there is now improved survival among patients with prostate cancer in the U.S., including among men with advanced disease. “Patients tend to live long enough after a prostate cancer diagnosis for non–cancer-related comorbidities to be associated with their overall survival,” they write.

The editorialists agree: Prostate cancer “has a high long-term survival rate compared with almost all other cancer types and signals the need for greater holistic care for patients.”

As noted above, cardiovascular diseases were the most common cause of nonprostate cancer–related deaths in the new study.

As in the management of other cancers, there is concern among clinicians and researchers about the cardiotoxic effects of prostate cancer treatments.

The study authors point to a 2017 analysis that showed that men with prostate cancer and no prior cardiac disease had greater risk of heart failure after taking androgen deprivation therapy (ADT), a common treatment used when the disease recurs after definitive treatment. Another study suggested an association between cardiotoxic effects of ADT and myocardial infarction regardless of medical history in general.

The authors of the current study say that such findings highlight “the importance of multidisciplinary care for such patients and the role of primary care physicians in optimizing cardiovascular risk prevention and providing early referrals to cardiologists.”

Further, the team says that tailoring “ADT to each patient’s needs may be associated with improved survival, especially for patients with factors associated with cardiovascular disease.”

Who should lead the way in multidisciplinary care? “The answer probably is case-by-case,” said Dr. Alhalabi, adding that it might depend on the presence of underlying morbidities such as cardiovascular disease and COPD.

“It is also important for the oncologist (‘the gatekeeper’) to try to mitigate the potential metabolic effects of hormonal deprivation therapy such as weight gain, decreased muscle mass, hyperlipidemia, etc.,” he added.

The study had no specific funding. The study authors and editorialists have disclosed no relevant financial relationships.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

The decades-long search for a safe, effective adjuvant therapy for patients with resected kidney cancer at high risk of recurrence appears to have taken a big step in the right direction, according to expert opinion.

The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.

The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.

For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.

The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.

Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.

That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.

Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.

“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.

To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”

Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.

“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.

Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.

In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”

KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.

A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.

“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.
 

Study details

KEYNOTE-564 involved 996 patients with clear-cell RCC at high risk for recurrence after nephrectomy, with or without metastasectomy. They were randomly assigned in a 1:1 ratio to receive a 200-mg dose of adjuvant pembrolizumab or placebo given intravenously once every 3 weeks for up to 17 cycles for approximately 1 year.

The vast majority of patients enrolled in the study had localized disease with no evidence of metastases (M0) and intermediate to high or high risk of disease recurrence after partial or complete nephrectomy. However, 5.8% of patients in both the pembrolizumab and placebo groups had M1 NED (metastatic stage 1, no evidence of disease) status after nephrectomy and resection of metastatic lesions. These patients were also at intermediate to high or high risk of recurrence.

The benefit of pembrolizumab, compared with placebo, was maintained in this subgroup, said the investigators. “At this point, we continue to look at the data, but we know that there was a benefit for DFS in the population we included,” said Dr. Choueiri. “When we looked at several subgroups such as PD-L1 status, geography, gender, performance status, M0/M1, all HRs were less than 1 suggesting benefit from pembrolizumab over placebo.”

“Subset analyses by stage are going to be important to determine which group of patients will derive the most benefit,” asserted Dr. McKay. “While those with M1 NED appear to derive benefit with HR for DFS of 0.29, those with M1 NED comprise a small percentage of patient enrolled in the trial.”

Studies exploring tissue- and blood-based biomarkers, including circulating tumor DNA, will be key to identify patients at highest risk for recurrence or adjuvant treatment, Dr. McKay emphasized. “The adoption of adjuvant immune checkpoint inhibitors brings along new questions regarding patient selection, therapeutic use in patients with non–clear-cell renal cell carcinoma, and systemic treatment after recurrence during or after the receipt of adjuvant therapy.”

KEYNOTE-564 was funded by Merck. Multiple study authors including Dr. Choueiri have financial ties to the pharmaceutical industry, including Merck.

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

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

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

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

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

A large, real-world test of face masks in Bangladesh shows that masks work to reduce community spread of COVID-19. It also shows that surgical masks are more effective than cloth face coverings.

OsakaWayne Studios/Moment

The study, which was published ahead of peer review, demonstrates the power of careful investigation and offers a host of lessons about mask wearing that will be important worldwide. One key finding of the study, for example, is that wearing a mask doesn’t lead people to abandon social distancing, something public health officials had feared might happen if masks gave people a false sense of security.

“What we really were able to achieve is to demonstrate that masks are effective against COVID-19, even under a rigorous and systematic evaluation that was done in the throes of the pandemic,” said Ashley Styczynski, MD, who was an infectious disease fellow at Stanford (Calif.) University when she collaborated on the study with other colleagues at Stanford, Yale, and Innovations for Poverty Action, a large research and policy nonprofit organization that currently works in 22 countries.

“And so, I think people who have been holding out on wearing masks because [they] felt like there wasn’t enough evidence for it, we’re hoping this will really help bridge that gap for them,” she said.

It included more than 600 unions – or local governmental districts in Bangladesh – and roughly 340,000 people.

Half of the districts were given cloth or surgical face masks along with continual reminders to wear them properly; the other half were tracked with no intervention. Blood tests of people who developed symptoms during the study verified their infections.

Compared to villages that didn’t mask, those in which masks of any type were worn had about 9% fewer symptomatic cases of COVID-19. The finding was statistically significant and was unlikely to have occurred by chance alone.

“Somebody could read this study and say, ‘OK, you reduced COVID-19 by 9%. Big deal.’ And what I would respond to that would be that, if anything, we think that that is a substantial underestimate,” Dr. Styczynski said.

One reason they think they underestimated the effectiveness of masks is that they tested only people who were having symptoms, so people who had only very mild or asymptomatic infections were missed.

Another reason is that, among people who had symptoms, only one-third agreed to undergo a blood test. The effect may have been bigger had participation been universal.

Local transmission may have played a role, too. Rates of COVID-19 in Bangladesh were relatively low during the study. Most infections were caused by the B.1.1.7, or Alpha, variant.

Since then, Delta has taken over. Delta is thought to be more transmissible, and some studies have suggested that people infected with Delta shed more viral particles. Masks may be more effective when more virus is circulating.

The investigators also found important differences by age and by the type of mask. Villages in which surgical masks were worn had 11% fewer COVID-19 cases than villages in which masks were not worn. In villages in which cloth masks were worn, on the other hand, infections were reduced by only 5%.

The cloth masks were substantial. Each had three layers – two layers of fabric with an outer layer of polypropylene. On testing, the filtration efficiency of the cloth masks was only about 37%, compared with 95% for the three-layer surgical masks, which were also made of polypropylene.

Masks were most effective for older individuals. People aged 50-60 years who wore surgical masks were 23% less likely to test positive for COVID, compared with their peers who didn’t wear masks. For people older than 60, the reduction in risk was greater – 35%.
 

Rigorous research

The study took place over a period of 8 weeks in each district. The interventions were rolled out in waves, with the first starting in November 2020 and the last in January 2021.

Investigators gave each household free cloth or surgical face masks and showed families a video about proper mask wearing with promotional messages from the prime minister, a head imam, and a national cricket star. They also handed out free masks.

Previous studies have shown that people aren’t always truthful about wearing masks in public. In Kenya, for example, 88% of people answering a phone survey said that they wore masks regularly, but researchers determined that only 10% of them actually did so.

Investigators in the Bangladesh study didn’t just ask people if they’d worn masks, they stationed themselves in public markets, mosques, tea stalls, and on roads that were the main entrances to the villages and took notes.

They also tested various ways to educate people and to remind them to wear masks. They found that four factors were effective at promoting the wearing of masks, and they gave them an acronym – NORM.

• N for no-cost masks.
• O for offering information through the video and local leaders.
• R for regular reminders to people by investigators who stand in public markets and offer masks or encourage anyone who wasn’t wearing one or wasn’t wearing it correctly.
• M for modeling, in which local leaders, such as imams, wear masks and remind their followers to wear them.

These four measures tripled the wearing of masks in the intervention communities, from a baseline level of 13% to 42%. People continued to wear their masks properly for about 2 weeks after the study ended, indicating that they’d gotten used to wearing them.

Dr. Styczynski said that nothing else – not text message reminders, or signs posted in public places, or local incentives – moved the needle on mask wearing.
 

Saved lives and money

The study found that the strategy was cost effective, too. Giving masks to a large population and getting people to use them costs about $10,000 per life saved from COVID, on par with the cost of deploying mosquito nets to save people from malaria, Dr. Styczynski said.

“I think that what we’ve been able to show is that this is a really important tool to be used globally, especially as countries have delays in getting access to vaccines and rolling them out,” she said.

Dr. Styczynski said masks will continue to be important even in countries such as the United States, where vaccines aren’t stopping transmission 100% and there are still large portions of the population who are unvaccinated, such as children.

“If we want to reduce COVID-19 here, it’s really important that we consider the ongoing utility of masks, in addition to vaccines, and not really thinking of them as one or the other,” she said.

The study was funded by a grant from GiveWell.org. The funder had no role in the study design, interpretation, or the decision to publish.

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

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Atopic dermatitis (AD) is an incredibly common chronic skin disease, affecting up to 25% of children and 7% of adults in the United States.^1,2 Despite the prevalence of this disease and its impact on patient quality of life, research and scholarly work in AD has been limited until recent years. A PubMed search of articles indexed for MEDLINE using the term atopic dermatitis showed that there were fewer than 500 articles published in 2000 and 965 in 2010; with our more recent acceleration in research, there were 2168 articles published in 2020 and more than 1300 published in just the first half of 2021 (through June). This new research includes insights into the pathogenesis of AD and study of the disease impact and comorbidities as well as an extensive amount of drug development and clinical trial work for new topical and systemic therapies.

New Agents to Treat AD

The 2016 approval of crisaborole,³ a phosphodiesterase 4 inhibitor, followed by the approval of dupilumab, an IL-4 and IL-13 pathway inhibitor and the first biologic agent approved for AD,⁴ ushered in a new age of therapy. We currently are awaiting the incorporation of a new set of topical nonsteroidal agents, oral Janus kinase (JAK) inhibitors, and new biologic agents for AD, several of which have completed phase 3 trials and extended safety evaluations. How these new drugs will impact our standard treatment across the spectrum of care for AD is not yet known.

The emergence of new systemic therapies is timely, as the most used systemic medications previously were oral corticosteroids, despite their use being advised against in standard practice guidelines. Other agents such as methotrexate, cyclosporine, azathioprine, and mycophenolate are discussed in the literature and AD treatment guidelines as being potentially useful, though absence of US Food and Drug Administration (FDA) approval and the need for frequent laboratory monitoring, as well as drug-specific side effects and an increased risk of infection, limit their use in the United States, especially in pediatric and adolescent populations.⁵

The approval of dupilumab as a systemic therapy—initially for adults and subsequently for teenagers (12–17 years of age) and then children (6–11 years of age)—has markedly influenced the standard of care for moderate to severe AD. This agent has been shown to have a considerable impact on disease severity and quality of life, with a good safety profile and the added benefit of not requiring continuous (or any) laboratory monitoring.^6-8 Ongoing studies of dupilumab in children (ClinicalTrials.gov identifiers NCT02612454, NCT03346434), including those younger than 1 year,⁹ raise the question of how commonly this medication might be incorporated into care across the entire age spectrum of patients with AD. What standards will there be for assessment of severity, disease impact, and persistence to warrant use in younger ages? Will early treatment with novel systemic agents change the overall course of the disease and minimize the development of comorbidities? The answers to these questions remain to be seen.

JAK Inhibitors for AD
Additional novel therapeutics currently are undergoing studies for treatment of AD, most notably the oral JAK inhibitors upadacitinib,¹⁰ baricitinib,¹¹ and abrocitinib.¹² Each of these agents has completed phase 3 trials for AD. Two of these agents—upadacitinib and baricitinib—have prior FDA approval for use in other disease states. Of note, baricitinib is already approved for treatment of moderate to severe AD in adults in more than 40 countries¹³; however, the use of these agents in other diseases brings about concerns of malignancy, severe infection, and thrombosis. In the clinical trials for AD, many of these events have not been seen, but the number of patients treated is limited, and longer-term safety assessment is important.^10,11

How will the oral JAK inhibitors be incorporated into care compared to biologic agents such as dupilumab? Tolerance and more serious potential adverse events are concerns, with nausea, headaches, and acneform eruptions being associated with some of the medications, in addition to potential issues with herpes simplex and zoster infections. However, oral JAK inhibitors have the benefit of not requiring injections, something that many patients may prefer, and data show that these drugs generally are associated with a rapid reduction in pruritus and, depending on the drug, very quick and profound effects on objective signs of AD.^10-12 Two head-to-head studies have been completed comparing dupilumab to oral JAK inhibitors in adults: the JADE COMPARE trial examining dupilumab vs abrocitinib¹² and the Heads UP trial comparing dupilumab vs upadacitinib.¹⁴ Compared to dupilumab, higher-dose abrocitinib showed more rapid responses, superiority in itch response, and similarity or superiority in other outcomes depending on the time point of the evaluation. Adverse event profiles differed; for example, abrocitinib was associated with more nausea, acneform eruptions, and herpes zoster, while dupilumab had higher rates of conjunctivitis.¹² Upadacitinib, which was only studied at higher dosing (30 mg daily), showed superiority to dupilumab in itch response and in improvement in AD severity in multiple outcome measures; however, there were increases in serious infections, eczema herpeticum, herpes zoster, and laboratory-related adverse events.¹⁴ Dupilumab has the advantage of studies of extended use along with real-world experience, generally with excellent safety and tolerance other than injection-site reactions and conjunctivitis.⁸ Biologics targeting IL-13—tralokinumab and lebrikizumab—also are to be added to our armamentarium.^15,16 The addition of these agents and JAK inhibitors as new systemic treatment options points to the quickly evolving future of AD treatment for patients with extensive disease.

New topical therapies in development provide even more treatment options. New nonsteroidal topicals include topical JAK inhibitors such as ruxolitinib¹⁷; tapinarof,¹⁸ an aryl hydrocarbon receptor modulator; and phosphodiesterase 4 inhibitors. These agents may be useful either as monotherapy, as studied, potentially without the regional limitations associated with stronger topical corticosteroids, but also should be useful in clinical practice as part of therapeutic regimens with other topical steroid and nonsteroidal agents.

The Microbiome and AD

In addition, research looking at topical microbes as specific interventions that may mediate the microbiome and inflammation of AD are intriguing. A recent phase 1 trial from the University of California San Diego¹⁹ indicated that topical bacteriotherapy directed at decreasing Staphylococcus aureus may provide an impact in AD. Observations by Kong et al²⁰ showed that gram-negative microbiome differences are seen in AD patients compared to unaffected individuals, which has fueled studies showing that Roseomonas mucosa, a gram-negative skin commensal, when applied as a topical live biotherapeutic agent has improved disease severity in children and adults with AD.²¹ Although further studies are underway, these initial data suggest a role for microbiome-modifying therapies as AD treatment.

Chronic Hand Eczema

Chronic hand eczema (CHE), which has considerable overlap with AD in many patients, especially children and adolescents,^22-24 is another area of interesting research. This high-prevalence condition is associated with allergic and irritant contact dermatitis^24-26—conditions that are both considered alternative diagnoses for and exacerbators of AD²⁷—and is a disease process currently being targeted for new therapies. Delgocitinib (NCT04872101, NCT04871711), the novel JAK inhibitor ARQ-252 (NCT04378569), among other topical agents, as well as systemic therapeutics such as gusacitinib (NCT03728504), are in active trials for CHE. Given CHE’s impact on quality of life²⁸ and its overlap with AD, investigation into this disorder can help drive future AD research as well as lead to better knowledge and treatment of CHE.

Final Thoughts

Despite the promising results of these myriad new therapies in AD, there are many factors that influence how and when we use these drugs, including their approval status, FDA labeling, and the ability of patients to access and afford treatment. Additionally, continued study is needed to evaluate the long-term safety and extended efficacy of newer drugs, such as the oral JAK inhibitors. Despite these hurdles, the current landscape of research and development is rapidly evolving. Compared to the many years when only one main group of therapies was a reasonable option for patients, the future of AD treatment looks bright.

Several health care-associated infections in U.S. hospitals spiked in 2020 compared to the previous year, according to a Centers for Disease Control and Prevention analysis published Sept. 2 in Infection Control and Hospital Epidemiology. Soaring hospitalization rates, sicker patients who required more frequent and intense care, and staffing and supply shortages caused by the COVID-19 pandemic are thought to have contributed to this increase.

This is the first increase in health care–associated infections since 2015.

These findings “are a reflection of the enormous stress that COVID has placed on our health care system,” Arjun Srinivasan, MD (Capt, USPHS), the associate director of the CDC’s Health care-Associated Infection Prevention Programs, Atlanta, told this news organization. He was not an author of the article, but he supervised the research. “We don’t want anyone to read this report and think that it represents a failure of the individual provider or a failure of health care providers in this country in their care of COVID patients,” he said. He noted that health care professionals have provided “tremendously good care to patients under extremely difficult circumstances.”

“People don’t fail – systems fail – and that’s what happened here,” he said. “Our systems that we need to have in place to prevent health care–associated infection simply were not as strong as they needed to be to survive this challenge.”

In the study, researchers used data reported to the National Healthcare Safety Network, the CDC’s tracking system for health care–associated infections. The team compared national standard infection ratios – calculated by dividing the number of reported infections by the number of predicted infections – between 2019 and 2020 for six routinely tracked events:

• Central line–associated bloodstream infections.
• Catheter-associated urinary tract infections (CAUTIs).
• Ventilator-associated events (VAEs).
• Infections associated with colon surgery and abdominal hysterectomy.
• Clostridioides difficile infections.
• Methicillin-resistant Staphylococcus aureus (MRSA) infections.

Infections were estimated using regression models created with baseline data from 2015.

“The new report highlights the need for health care facilities to strengthen their infection prevention programs and support them with adequate resources so that they can handle emerging threats to public health, while at the same time ensuring that gains made in combating HAIs [health care–associated infections] are not lost,” said the Association for Professionals in Infection Control and Epidemiology in a statement.

The analysis revealed significant national increases in central line–associated bloodstream infections, CAUTIs, VAEs, and MRSA infections in 2020 compared to 2019. Among all infection types, the greatest increase was in central-line infections, which were 46% to 47% higher in the third quarter and fourth quarter (Q4) of 2020 relative to the same periods the previous year. VAEs rose by 45%, MRSA infections increased by 34%, and CAUTIs increased by 19% in Q4 of 2020 compared to 2019.

The influx of sicker patients in hospitals throughout 2020 led to more frequent and longer use of medical devices such as catheters and ventilators. The use of these devices increases risk for infection, David P. Calfee, MD, chief medical epidemiologist at the New York–Presbyterian/Weill Cornell Medical Center, said in an interview. He is an editor of Infection Control and Hospital Epidemiology and was not involved with the study. Shortages in personal protective equipment and crowded intensive care units could also have affected how care was delivered, he said. These factors could have led to “reductions in the ability to provide some of the types of care that are needed to optimally reduce the risk of infection.”

There was either no change or decreases in infections associated with colon surgery or abdominal hysterectomy, likely because there were fewer elective surgeries performed, said Dr. Srinivasan. C. difficile–associated infections also decreased throughout 2020 compared to the previous year. Common practices to prevent the spread of COVID-19 in hospitals, such as environmental cleaning, use of personal protective equipment, and patient isolation, likely helped to curb the spread of C. difficile. Although these mitigating procedures do help protect against MRSA infection, many other factors, notably, the use of medical devices such as ventilators and catheters, can increase the risk for MRSA infection, Dr. Srinivasan added.

Although more research is needed to identify the reasons for these spikes in infection, the findings help quantify the scope of these increases across the United States, Dr. Calfee said. The data allow hospitals and health care professionals to “look back at what we did and then think forward in terms of what we can do different in the future,” he added, “so that these stresses to the system have less of an impact on how we are able to provide care.”

Dr. Srinivasan and Dr. Calfee report no relevant financial relationships.

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

Several health care-associated infections in U.S. hospitals spiked in 2020 compared to the previous year, according to a Centers for Disease Control and Prevention analysis published Sept. 2 in Infection Control and Hospital Epidemiology. Soaring hospitalization rates, sicker patients who required more frequent and intense care, and staffing and supply shortages caused by the COVID-19 pandemic are thought to have contributed to this increase.

This is the first increase in health care–associated infections since 2015.

These findings “are a reflection of the enormous stress that COVID has placed on our health care system,” Arjun Srinivasan, MD (Capt, USPHS), the associate director of the CDC’s Health care-Associated Infection Prevention Programs, Atlanta, told this news organization. He was not an author of the article, but he supervised the research. “We don’t want anyone to read this report and think that it represents a failure of the individual provider or a failure of health care providers in this country in their care of COVID patients,” he said. He noted that health care professionals have provided “tremendously good care to patients under extremely difficult circumstances.”

“People don’t fail – systems fail – and that’s what happened here,” he said. “Our systems that we need to have in place to prevent health care–associated infection simply were not as strong as they needed to be to survive this challenge.”

In the study, researchers used data reported to the National Healthcare Safety Network, the CDC’s tracking system for health care–associated infections. The team compared national standard infection ratios – calculated by dividing the number of reported infections by the number of predicted infections – between 2019 and 2020 for six routinely tracked events:

• Central line–associated bloodstream infections.
• Catheter-associated urinary tract infections (CAUTIs).
• Ventilator-associated events (VAEs).
• Infections associated with colon surgery and abdominal hysterectomy.
• Clostridioides difficile infections.
• Methicillin-resistant Staphylococcus aureus (MRSA) infections.

Infections were estimated using regression models created with baseline data from 2015.

“The new report highlights the need for health care facilities to strengthen their infection prevention programs and support them with adequate resources so that they can handle emerging threats to public health, while at the same time ensuring that gains made in combating HAIs [health care–associated infections] are not lost,” said the Association for Professionals in Infection Control and Epidemiology in a statement.

The analysis revealed significant national increases in central line–associated bloodstream infections, CAUTIs, VAEs, and MRSA infections in 2020 compared to 2019. Among all infection types, the greatest increase was in central-line infections, which were 46% to 47% higher in the third quarter and fourth quarter (Q4) of 2020 relative to the same periods the previous year. VAEs rose by 45%, MRSA infections increased by 34%, and CAUTIs increased by 19% in Q4 of 2020 compared to 2019.

The influx of sicker patients in hospitals throughout 2020 led to more frequent and longer use of medical devices such as catheters and ventilators. The use of these devices increases risk for infection, David P. Calfee, MD, chief medical epidemiologist at the New York–Presbyterian/Weill Cornell Medical Center, said in an interview. He is an editor of Infection Control and Hospital Epidemiology and was not involved with the study. Shortages in personal protective equipment and crowded intensive care units could also have affected how care was delivered, he said. These factors could have led to “reductions in the ability to provide some of the types of care that are needed to optimally reduce the risk of infection.”

There was either no change or decreases in infections associated with colon surgery or abdominal hysterectomy, likely because there were fewer elective surgeries performed, said Dr. Srinivasan. C. difficile–associated infections also decreased throughout 2020 compared to the previous year. Common practices to prevent the spread of COVID-19 in hospitals, such as environmental cleaning, use of personal protective equipment, and patient isolation, likely helped to curb the spread of C. difficile. Although these mitigating procedures do help protect against MRSA infection, many other factors, notably, the use of medical devices such as ventilators and catheters, can increase the risk for MRSA infection, Dr. Srinivasan added.

Although more research is needed to identify the reasons for these spikes in infection, the findings help quantify the scope of these increases across the United States, Dr. Calfee said. The data allow hospitals and health care professionals to “look back at what we did and then think forward in terms of what we can do different in the future,” he added, “so that these stresses to the system have less of an impact on how we are able to provide care.”

Dr. Srinivasan and Dr. Calfee report no relevant financial relationships.

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

Several health care-associated infections in U.S. hospitals spiked in 2020 compared to the previous year, according to a Centers for Disease Control and Prevention analysis published Sept. 2 in Infection Control and Hospital Epidemiology. Soaring hospitalization rates, sicker patients who required more frequent and intense care, and staffing and supply shortages caused by the COVID-19 pandemic are thought to have contributed to this increase.

This is the first increase in health care–associated infections since 2015.

These findings “are a reflection of the enormous stress that COVID has placed on our health care system,” Arjun Srinivasan, MD (Capt, USPHS), the associate director of the CDC’s Health care-Associated Infection Prevention Programs, Atlanta, told this news organization. He was not an author of the article, but he supervised the research. “We don’t want anyone to read this report and think that it represents a failure of the individual provider or a failure of health care providers in this country in their care of COVID patients,” he said. He noted that health care professionals have provided “tremendously good care to patients under extremely difficult circumstances.”

“People don’t fail – systems fail – and that’s what happened here,” he said. “Our systems that we need to have in place to prevent health care–associated infection simply were not as strong as they needed to be to survive this challenge.”

In the study, researchers used data reported to the National Healthcare Safety Network, the CDC’s tracking system for health care–associated infections. The team compared national standard infection ratios – calculated by dividing the number of reported infections by the number of predicted infections – between 2019 and 2020 for six routinely tracked events:

• Central line–associated bloodstream infections.
• Catheter-associated urinary tract infections (CAUTIs).
• Ventilator-associated events (VAEs).
• Infections associated with colon surgery and abdominal hysterectomy.
• Clostridioides difficile infections.
• Methicillin-resistant Staphylococcus aureus (MRSA) infections.

Infections were estimated using regression models created with baseline data from 2015.

“The new report highlights the need for health care facilities to strengthen their infection prevention programs and support them with adequate resources so that they can handle emerging threats to public health, while at the same time ensuring that gains made in combating HAIs [health care–associated infections] are not lost,” said the Association for Professionals in Infection Control and Epidemiology in a statement.

The analysis revealed significant national increases in central line–associated bloodstream infections, CAUTIs, VAEs, and MRSA infections in 2020 compared to 2019. Among all infection types, the greatest increase was in central-line infections, which were 46% to 47% higher in the third quarter and fourth quarter (Q4) of 2020 relative to the same periods the previous year. VAEs rose by 45%, MRSA infections increased by 34%, and CAUTIs increased by 19% in Q4 of 2020 compared to 2019.

The influx of sicker patients in hospitals throughout 2020 led to more frequent and longer use of medical devices such as catheters and ventilators. The use of these devices increases risk for infection, David P. Calfee, MD, chief medical epidemiologist at the New York–Presbyterian/Weill Cornell Medical Center, said in an interview. He is an editor of Infection Control and Hospital Epidemiology and was not involved with the study. Shortages in personal protective equipment and crowded intensive care units could also have affected how care was delivered, he said. These factors could have led to “reductions in the ability to provide some of the types of care that are needed to optimally reduce the risk of infection.”

There was either no change or decreases in infections associated with colon surgery or abdominal hysterectomy, likely because there were fewer elective surgeries performed, said Dr. Srinivasan. C. difficile–associated infections also decreased throughout 2020 compared to the previous year. Common practices to prevent the spread of COVID-19 in hospitals, such as environmental cleaning, use of personal protective equipment, and patient isolation, likely helped to curb the spread of C. difficile. Although these mitigating procedures do help protect against MRSA infection, many other factors, notably, the use of medical devices such as ventilators and catheters, can increase the risk for MRSA infection, Dr. Srinivasan added.

Although more research is needed to identify the reasons for these spikes in infection, the findings help quantify the scope of these increases across the United States, Dr. Calfee said. The data allow hospitals and health care professionals to “look back at what we did and then think forward in terms of what we can do different in the future,” he added, “so that these stresses to the system have less of an impact on how we are able to provide care.”

Dr. Srinivasan and Dr. Calfee report no relevant financial relationships.

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

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

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

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

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

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

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

In a small study, intravenous administration of the beta-blocker metoprolol to critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) safely blunted lung inflammation associated with the disease.

Metoprolol administration also resulted in better oxygenation and fewer days on intensive mechanical ventilation and in the ICU, compared with no treatment.

These data suggest that metoprolol repurposing for the treatment of ARDS in COVID-19 patients is a safe and inexpensive strategy with the potential to improve outcomes, the researchers said.

“Metoprolol repurposing for the treatment of ARDS associated with COVID-19 is a safe and cheap intervention that can help to alleviate the massive personal and health care burden associated with the pandemic,” they concluded.

The results, from the MADRID-COVID pilot trial from Agustin Clemente-Moragon, BSc, Centro National de Investigaciones Cardiovasculares, Madrid, and colleagues, were published online Aug. 30, 2021, in the Journal of the American College of Cardiology.

In previous work, the researchers showed that metoprolol, but not other clinically available intravenous beta-blockers, abrogates neutrophil-driven exacerbated inflammation, neutrophil-platelet interaction, and formation of neutrophil extracellular traps in a mouse model of acute lung injury.

These results prompted the current pilot trial in 20 patients, ages 18-80 years, with COVID-19–associated ARDS.

Randomization was stratified by age (59 and younger vs. 60 and older), history of hypertension (yes or no), and circulating neutrophil counts (<6,000 vs. ≥6,000). Bronchoalveolar lavage (BAL) fluid and blood samples were obtained from patients at randomization and 24 hours after the third metoprolol dose in the treatment group, and on day 4 in controls.

Because of the cardiovascular effects of metoprolol, patients were monitored invasively and by echocardiography, the authors noted.

As expected, metoprolol significantly reduced heart rate (P < .01) and systolic blood pressure (P < .05), although both remained within the physiological range. Echocardiography showed no deterioration of cardiac function after metoprolol treatment.

To assess the ability of metoprolol to address neutrophil-mediated exacerbated lung inflammation, the researchers analyzed leukocyte populations in BAL samples by flow cytometry at baseline and on day 4.

At baseline, the metoprolol and control groups showed no differences in BAL neutrophil content. But on day 4, after 3 days of treatment with metoprolol, neutrophil content was significantly lower in the metoprolol group (median, 14.3 neutrophils/mcL) than in the control group (median, 397 neutrophils/mcL).

Metoprolol-treated patients also had lower total inflammatory-cell content and lower monocyte/macrophage content. Lymphocytes did not differ between the groups.

The investigators also explored the impact of metoprolol on the chemokine, monocyte chemoattractant protein–1 (MCP-1), as it has been shown to promote pulmonary fibrosis in late-stage ARDS.

They found that MCP-1 was significantly attenuated after 3 days of metoprolol treatment. At baseline, the median MCP-1 level was 298 pg/mL; on day 4 after metoprolol, it was 203 pg/mL (P = .009).

MCP-1 levels remained unchanged in control patients.
 

An elegant study

In an accompanying editorial, Mourad H. Senussi, MD, assistant professor at Baylor College of Medicine, Houston, wrote: “Although the study has a small sample size, we commend the authors, who attempt to shed light on the important pathophysiological underpinnings that help establish biological plausibility for this inexpensive, safe, and widely available medication.”

In an interview with this news organization, Dr. Senussi added that metoprolol is not itself something primarily used to treat COVID-19 per se. “Rather, the drug blunts the sympathetic-host response. There is a fine balance between that sympathetic surge that is helpful to the body, and then a sympathetic surge that if left unchecked, can lead to significant damage. And so, I think this study really shows that medications like metoprolol can help blunt that initial sympathetic effect.”

A larger study is “absolutely” warranted, he added, “this is a drug that is readily available, safe, and inexpensive. The study design here was simple and most importantly, showed biological plausibility.”

Dr. Senussi also noted that, although the benefit was noted in COVID-19 patients, the study sets the groundwork for further research in the use of beta-blockade in the critically ill. “Further studies are needed to elucidate and identify where along the inflammatory spectrum these critically ill patients lie, which patients would benefit from beta-blockers, and at what time point during their hospital stay.”

The MADRID-COVID authors and Dr. Senussi disclosed no relevant financial relationships.

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

In a small study, intravenous administration of the beta-blocker metoprolol to critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) safely blunted lung inflammation associated with the disease.

Metoprolol administration also resulted in better oxygenation and fewer days on intensive mechanical ventilation and in the ICU, compared with no treatment.

These data suggest that metoprolol repurposing for the treatment of ARDS in COVID-19 patients is a safe and inexpensive strategy with the potential to improve outcomes, the researchers said.

“Metoprolol repurposing for the treatment of ARDS associated with COVID-19 is a safe and cheap intervention that can help to alleviate the massive personal and health care burden associated with the pandemic,” they concluded.

The results, from the MADRID-COVID pilot trial from Agustin Clemente-Moragon, BSc, Centro National de Investigaciones Cardiovasculares, Madrid, and colleagues, were published online Aug. 30, 2021, in the Journal of the American College of Cardiology.

In previous work, the researchers showed that metoprolol, but not other clinically available intravenous beta-blockers, abrogates neutrophil-driven exacerbated inflammation, neutrophil-platelet interaction, and formation of neutrophil extracellular traps in a mouse model of acute lung injury.

These results prompted the current pilot trial in 20 patients, ages 18-80 years, with COVID-19–associated ARDS.

Randomization was stratified by age (59 and younger vs. 60 and older), history of hypertension (yes or no), and circulating neutrophil counts (<6,000 vs. ≥6,000). Bronchoalveolar lavage (BAL) fluid and blood samples were obtained from patients at randomization and 24 hours after the third metoprolol dose in the treatment group, and on day 4 in controls.

Because of the cardiovascular effects of metoprolol, patients were monitored invasively and by echocardiography, the authors noted.

As expected, metoprolol significantly reduced heart rate (P < .01) and systolic blood pressure (P < .05), although both remained within the physiological range. Echocardiography showed no deterioration of cardiac function after metoprolol treatment.

To assess the ability of metoprolol to address neutrophil-mediated exacerbated lung inflammation, the researchers analyzed leukocyte populations in BAL samples by flow cytometry at baseline and on day 4.

At baseline, the metoprolol and control groups showed no differences in BAL neutrophil content. But on day 4, after 3 days of treatment with metoprolol, neutrophil content was significantly lower in the metoprolol group (median, 14.3 neutrophils/mcL) than in the control group (median, 397 neutrophils/mcL).

Metoprolol-treated patients also had lower total inflammatory-cell content and lower monocyte/macrophage content. Lymphocytes did not differ between the groups.

The investigators also explored the impact of metoprolol on the chemokine, monocyte chemoattractant protein–1 (MCP-1), as it has been shown to promote pulmonary fibrosis in late-stage ARDS.

They found that MCP-1 was significantly attenuated after 3 days of metoprolol treatment. At baseline, the median MCP-1 level was 298 pg/mL; on day 4 after metoprolol, it was 203 pg/mL (P = .009).

MCP-1 levels remained unchanged in control patients.
 

An elegant study

In an accompanying editorial, Mourad H. Senussi, MD, assistant professor at Baylor College of Medicine, Houston, wrote: “Although the study has a small sample size, we commend the authors, who attempt to shed light on the important pathophysiological underpinnings that help establish biological plausibility for this inexpensive, safe, and widely available medication.”

In an interview with this news organization, Dr. Senussi added that metoprolol is not itself something primarily used to treat COVID-19 per se. “Rather, the drug blunts the sympathetic-host response. There is a fine balance between that sympathetic surge that is helpful to the body, and then a sympathetic surge that if left unchecked, can lead to significant damage. And so, I think this study really shows that medications like metoprolol can help blunt that initial sympathetic effect.”

A larger study is “absolutely” warranted, he added, “this is a drug that is readily available, safe, and inexpensive. The study design here was simple and most importantly, showed biological plausibility.”

Dr. Senussi also noted that, although the benefit was noted in COVID-19 patients, the study sets the groundwork for further research in the use of beta-blockade in the critically ill. “Further studies are needed to elucidate and identify where along the inflammatory spectrum these critically ill patients lie, which patients would benefit from beta-blockers, and at what time point during their hospital stay.”

The MADRID-COVID authors and Dr. Senussi disclosed no relevant financial relationships.

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

In a small study, intravenous administration of the beta-blocker metoprolol to critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) safely blunted lung inflammation associated with the disease.

Metoprolol administration also resulted in better oxygenation and fewer days on intensive mechanical ventilation and in the ICU, compared with no treatment.

These data suggest that metoprolol repurposing for the treatment of ARDS in COVID-19 patients is a safe and inexpensive strategy with the potential to improve outcomes, the researchers said.

“Metoprolol repurposing for the treatment of ARDS associated with COVID-19 is a safe and cheap intervention that can help to alleviate the massive personal and health care burden associated with the pandemic,” they concluded.

The results, from the MADRID-COVID pilot trial from Agustin Clemente-Moragon, BSc, Centro National de Investigaciones Cardiovasculares, Madrid, and colleagues, were published online Aug. 30, 2021, in the Journal of the American College of Cardiology.

In previous work, the researchers showed that metoprolol, but not other clinically available intravenous beta-blockers, abrogates neutrophil-driven exacerbated inflammation, neutrophil-platelet interaction, and formation of neutrophil extracellular traps in a mouse model of acute lung injury.

These results prompted the current pilot trial in 20 patients, ages 18-80 years, with COVID-19–associated ARDS.

Randomization was stratified by age (59 and younger vs. 60 and older), history of hypertension (yes or no), and circulating neutrophil counts (<6,000 vs. ≥6,000). Bronchoalveolar lavage (BAL) fluid and blood samples were obtained from patients at randomization and 24 hours after the third metoprolol dose in the treatment group, and on day 4 in controls.

Because of the cardiovascular effects of metoprolol, patients were monitored invasively and by echocardiography, the authors noted.

As expected, metoprolol significantly reduced heart rate (P < .01) and systolic blood pressure (P < .05), although both remained within the physiological range. Echocardiography showed no deterioration of cardiac function after metoprolol treatment.

To assess the ability of metoprolol to address neutrophil-mediated exacerbated lung inflammation, the researchers analyzed leukocyte populations in BAL samples by flow cytometry at baseline and on day 4.

At baseline, the metoprolol and control groups showed no differences in BAL neutrophil content. But on day 4, after 3 days of treatment with metoprolol, neutrophil content was significantly lower in the metoprolol group (median, 14.3 neutrophils/mcL) than in the control group (median, 397 neutrophils/mcL).

Metoprolol-treated patients also had lower total inflammatory-cell content and lower monocyte/macrophage content. Lymphocytes did not differ between the groups.

The investigators also explored the impact of metoprolol on the chemokine, monocyte chemoattractant protein–1 (MCP-1), as it has been shown to promote pulmonary fibrosis in late-stage ARDS.

They found that MCP-1 was significantly attenuated after 3 days of metoprolol treatment. At baseline, the median MCP-1 level was 298 pg/mL; on day 4 after metoprolol, it was 203 pg/mL (P = .009).

MCP-1 levels remained unchanged in control patients.
 

An elegant study

In an accompanying editorial, Mourad H. Senussi, MD, assistant professor at Baylor College of Medicine, Houston, wrote: “Although the study has a small sample size, we commend the authors, who attempt to shed light on the important pathophysiological underpinnings that help establish biological plausibility for this inexpensive, safe, and widely available medication.”

In an interview with this news organization, Dr. Senussi added that metoprolol is not itself something primarily used to treat COVID-19 per se. “Rather, the drug blunts the sympathetic-host response. There is a fine balance between that sympathetic surge that is helpful to the body, and then a sympathetic surge that if left unchecked, can lead to significant damage. And so, I think this study really shows that medications like metoprolol can help blunt that initial sympathetic effect.”

A larger study is “absolutely” warranted, he added, “this is a drug that is readily available, safe, and inexpensive. The study design here was simple and most importantly, showed biological plausibility.”

Dr. Senussi also noted that, although the benefit was noted in COVID-19 patients, the study sets the groundwork for further research in the use of beta-blockade in the critically ill. “Further studies are needed to elucidate and identify where along the inflammatory spectrum these critically ill patients lie, which patients would benefit from beta-blockers, and at what time point during their hospital stay.”

The MADRID-COVID authors and Dr. Senussi disclosed no relevant financial relationships.

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

Latin American countries have a high rate of SARS-CoV-2 infection and some of the highest COVID-19 deaths worldwide. Brazil, Colombia, Argentina, and Mexico have reported the highest number of confirmed cases. More recently has been reported that in series form US and Europe the mortality of COVID-19 has not been as high as reported in other hematological conditions and the response to vaccination also has bene described as high. In a recent report, Pagnano et al. (Leuk Lymphoma. 2021) has recently reported the clinical evolution and outcome of COVID-19 in patients with chronic myeloid leukemia in Latin America. In an observational multicenter study with a total of 92 patients with COVID-19 between March and December 2020 with 26% of whom were severe or critical. Eighty-one patients recovered (88%), and 11 (11.9%) died from COVID-19. Almost half of them had at least one comorbidity. Patients with a major molecular response presented superior overall survival compared to patients with no major molecular response (91 vs. 61%, respectively; P = 0.004). Patients in treatment-free remission and receiving tyrosine kinase inhibitors showed higher survival rates (100 and 89%) than patients who underwent hematopoietic stem cell transplantation and those who did not receive tyrosine kinase inhibitors (50 and 33%).

Currently the most common reason for TKI discontinuation is intolerance. Ma et al (Leuk Res. 2021) reports the long-term outcomes associated with switch to an alternative TKI after first-line therapy with a 2GTKI. Of 232 patients who initiated a 2GTKI during the study period, 76 (33 %) switched to an alternative TKI. Reasons for switching included intolerance (79 %) and resistance (21 %). Among the 60 patients who switched due to intolerance, 53 (88 %) were able to achieve or maintain a major molecular response (MMR) with 5-year progression-free survival (PFS) 90.5 % (95 % CI 90.4–90.6 %). However, amongst the 16 patients who switched due to resistance, 8 patients (50 %) were able to achieve MMR with 5-year PFS 80.4 % (95 % CI 80.2–80.6 %). Most patients who switched due to intolerance remained on their second-line TKI. Patients who switch for intolerance continue to enjoy excellent long term clinical outcomes.

Latin American countries have a high rate of SARS-CoV-2 infection and some of the highest COVID-19 deaths worldwide. Brazil, Colombia, Argentina, and Mexico have reported the highest number of confirmed cases. More recently has been reported that in series form US and Europe the mortality of COVID-19 has not been as high as reported in other hematological conditions and the response to vaccination also has bene described as high. In a recent report, Pagnano et al. (Leuk Lymphoma. 2021) has recently reported the clinical evolution and outcome of COVID-19 in patients with chronic myeloid leukemia in Latin America. In an observational multicenter study with a total of 92 patients with COVID-19 between March and December 2020 with 26% of whom were severe or critical. Eighty-one patients recovered (88%), and 11 (11.9%) died from COVID-19. Almost half of them had at least one comorbidity. Patients with a major molecular response presented superior overall survival compared to patients with no major molecular response (91 vs. 61%, respectively; P = 0.004). Patients in treatment-free remission and receiving tyrosine kinase inhibitors showed higher survival rates (100 and 89%) than patients who underwent hematopoietic stem cell transplantation and those who did not receive tyrosine kinase inhibitors (50 and 33%).

Currently the most common reason for TKI discontinuation is intolerance. Ma et al (Leuk Res. 2021) reports the long-term outcomes associated with switch to an alternative TKI after first-line therapy with a 2GTKI. Of 232 patients who initiated a 2GTKI during the study period, 76 (33 %) switched to an alternative TKI. Reasons for switching included intolerance (79 %) and resistance (21 %). Among the 60 patients who switched due to intolerance, 53 (88 %) were able to achieve or maintain a major molecular response (MMR) with 5-year progression-free survival (PFS) 90.5 % (95 % CI 90.4–90.6 %). However, amongst the 16 patients who switched due to resistance, 8 patients (50 %) were able to achieve MMR with 5-year PFS 80.4 % (95 % CI 80.2–80.6 %). Most patients who switched due to intolerance remained on their second-line TKI. Patients who switch for intolerance continue to enjoy excellent long term clinical outcomes.

Latin American countries have a high rate of SARS-CoV-2 infection and some of the highest COVID-19 deaths worldwide. Brazil, Colombia, Argentina, and Mexico have reported the highest number of confirmed cases. More recently has been reported that in series form US and Europe the mortality of COVID-19 has not been as high as reported in other hematological conditions and the response to vaccination also has bene described as high. In a recent report, Pagnano et al. (Leuk Lymphoma. 2021) has recently reported the clinical evolution and outcome of COVID-19 in patients with chronic myeloid leukemia in Latin America. In an observational multicenter study with a total of 92 patients with COVID-19 between March and December 2020 with 26% of whom were severe or critical. Eighty-one patients recovered (88%), and 11 (11.9%) died from COVID-19. Almost half of them had at least one comorbidity. Patients with a major molecular response presented superior overall survival compared to patients with no major molecular response (91 vs. 61%, respectively; P = 0.004). Patients in treatment-free remission and receiving tyrosine kinase inhibitors showed higher survival rates (100 and 89%) than patients who underwent hematopoietic stem cell transplantation and those who did not receive tyrosine kinase inhibitors (50 and 33%).

Currently the most common reason for TKI discontinuation is intolerance. Ma et al (Leuk Res. 2021) reports the long-term outcomes associated with switch to an alternative TKI after first-line therapy with a 2GTKI. Of 232 patients who initiated a 2GTKI during the study period, 76 (33 %) switched to an alternative TKI. Reasons for switching included intolerance (79 %) and resistance (21 %). Among the 60 patients who switched due to intolerance, 53 (88 %) were able to achieve or maintain a major molecular response (MMR) with 5-year progression-free survival (PFS) 90.5 % (95 % CI 90.4–90.6 %). However, amongst the 16 patients who switched due to resistance, 8 patients (50 %) were able to achieve MMR with 5-year PFS 80.4 % (95 % CI 80.2–80.6 %). Most patients who switched due to intolerance remained on their second-line TKI. Patients who switch for intolerance continue to enjoy excellent long term clinical outcomes.