Psychological First Aid is an innovative program launched by the American Red Cross with the goal of addressing issues of concern such as those stemming from COVID-19–related stress. According to Red Cross mental health volunteer representative Deb Butman-Perkins, the program provides “a general overview of what does stress look like, how do we feel it, how do we recognize it in our bodies ... physical, emotional, spiritual, physiological, where does all that stress occur?”¹

The program brings a spotlight to the interdisciplinary nature of the stress response, especially with respect to the importance of developing the necessary coping skills during an ongoing crisis. However, to effectively evaluate and manage the overall stress response for psychiatric patients during quarantine conditions, as well as those who are formally diagnosed with COVID-19, clinicians also will need to revisit what we’ve learned about the hypothalamic-pituitary-adrenal (HPA) axis.

We know that the stress response – which varies somewhat across the spectrum – is necessary to ensure homeostatic regulation. A feedback loop is initiated at the receptor level, involving a myriad of hormones and chemical signals that bring forth the body’s “flight-or-fight” response. Hormones such as epinephrine/norepinephrine and cortisol are secreted by the HPA axis in reaction to the stress response, resulting in a spike in heart rate, blood pressure, and transient hyperglycemia, respectively. In particular, hyperglycemia provides immediate energy to muscles during a perceived crisis.²

In addition, prolonged exposure to living in quarantine can lead to feelings of isolation and estrangement – and excessive anxiety. Combined, those conditions may exert an indelible effect on the HPA axis – leading to a warped pattern of cortisol secretion with respect to baseline.³ (It has been noted in the literature that serum cortisol plays a protective role in thwarting off the effects of PTSD development. Consistent with this line of thinking, military personnel have been preemptively treated with high-dose cortisol during acute exposure.)

Prolonged exposure to psychosocial stressors also increases the overall risk of developing medical comorbidities. Patients who adopt maladaptive responses to traumatic events, for example, may experience dysregulation in eating behaviors and/or disordered sleep.⁴

In light of those realities, clinicians should explore the role of steroid therapy as a means of treating mental health patients experiencing psychological stress formation tied to ongoing quarantine conditions.
 

Challenges of neuroendocrine medications for COVID-19

COVID-19, caused by exposure to SARS-CoV-2, adeptly leverages the ACE2 receptor of the lungs as an entry point to evade the host’s defenses. It should be noted that the ACE2 protein is expressed on the cells of multiple organs of the body, including the adrenals, which are largely responsible for coordinating the stress response of the HPA axis.

Postmortem analysis from severe acute respiratory syndrome (SARS-CoV is also from the Coronaviridae family) patients indicates the presence of necrotic adrenal cells, further solidifying the association of the HPA axis to the COVID-19 disease state and pathophysiological course.⁵ Molecular mimicry of the adrenocorticotropic hormone allows SARS-CoV the ability to infiltrate the host’s defenses, in particular, the ability to mount a clinically apt cortisol stress response (e.g., hypocortisolism).As for those who survived the 2003 SARS outbreak, less than half of the patients have been observed to develop symptoms of frank hypocortisolism within a few months after exposure.

The World Health Organization recently endorsed the use of steroid therapy for critically ill COVID-19 patients, and an ongoing clinical trial is evaluating the safety and efficacy parameters of corticosteroids in COVID-19–exposed patients.

In addition, there is reason to believe that application of prophylactic steroids might affect the overall clinical course of COVID-19, thereby reducing mortality and morbidity rates in patients with severe presentation, such as septic shock. The rationale for this line of thought is based on the ability of glucocorticoids to suppress an ensuing cytokine storm by the virus in question.^5,6 In clinical practice, steroids have been used to treat a host of viral diseases, including influenza, respiratory syncytial virus, and Middle East respiratory syndrome coronavirus.

Aside from the selective use of corticosteroids, the medication regimen may incorporate ACE inhibitors and/or angiotensin receptor blockers (ARBs) because of COVID-19’s ability to activate the renin-angiotensin-aldosterone system with respect to the physiological stress response.

The interplay of the HPA axis with the sympathoadrenal system is responsible for adaptive behaviors in the individual. Disrupted feedback loops from prolonged activation are associated with numerous stress-based conditions in mental illness, namely, PTSD, anxiety, and mood disorders. We are concerned about frontline health care workers, who are particularly prone to chronic stress and burnout because of the cumbersome patient load and equipment shortage that have characterized the coronavirus crisis.

Timely administration of corticosteroids on a case-by-case basis would keep the cytokines at bay by precluding their undue activation of the HPA axis and corresponding cascade stress response. Steroids are also known to restore disrupted feedback loops at the level of the immune cells. However, because of conflicting reports concerning viral clearance in some SARS and COVID-19 studies, treatment with steroids may be limited to select patient populations with the necessary dose adjustments. Ongoing clinical trials will further elucidate upon the applicability of steroids as well as the role of other neuroendocrine agents, such as ACE inhibitors or ARBs, in the treatment of COVID-19.
 

Behavioral manifestations and psychosocial health

As far as the stress response is concerned, an analysis performed by researchers in China after the COVID-19 outbreak found gender disparities in symptom expression. In the study (n = 1,210) the researchers found in female citizens a greater frequency of behavioral manifestations, including acute stress reaction, and symptoms of anxiety and mood disorders – namely, depression.⁷ Patient perception and awareness of the perils of coronavirus typically varied across the spectrum; some individuals reportedly undermined and devalued their risk of contracting COVID-19 – these patients may benefit from therapeutic modalities, such as cognitive-behavioral therapy (CBT), as a means of challenging their firmly entrenched cognitive distortions. CBT is an effective tool in addressing maladaptive coping responses, because these strategies tend to correspond with poor prognosis with respect to overall mental health. Aside from CBT, the clinician may advise other behavioral techniques, such as relaxation training, with the aim of controlling the symptoms of mood and anxiety disorders.

We often take for granted general pandemic safety precautions, such as maintaining physical distancing coupled with engaging in regular hand hygiene and wearing masks, but these actions also are known to alleviate mental anguish. Access to accurate and easy-to-consume health information regarding COVID-19 is also associated with psychological well-being during the quarantine.⁸

An intriguing “phenomenon” has emerged in the form of “panic buying.”However, researchers reported in the peer-reviewed journal Nature Human Behaviour that this pattern of behaviors is not typical for those under distress and represents an overstated misnomer of sorts. According to Jay J. Van Bavel, PhD, and associates, prevailing reports from news outlets have skewed the features of a panic. “News stories that employ the language of panic often create the very phenomena that they purport to condemn,” Dr. Van Bavel and associates wrote. “They can foster the very individualism and competitiveness that turn sensible preparations into dysfunctional stockpiling and undermine the sense of collective purpose which facilitates people supporting one another during an emergency.”⁹

The researchers proceeded to highlight the scope of effective crisis leadership with respect to establishing a sense of communal “self-efficacy and hope.” The influence of organized leadership serves to solidify the structure of the community as a whole, allowing group members the opportunity to address the stressors of interest. Such leadership may mitigate the stress response by fostering a necessary, healthy set for stress management.

Strategies aimed at supporting mental health

Coping and stress management strategies may include the process of building virtual networks (e.g., social media platforms) because physical distancing may contribute toward further isolation and social estrangement. However, it should be noted that ideally social media consumption should be centered upon interactive enrichment activities that provide a suitable substitute for the absence of physical support systems. The goal is to facilitate meaningful relationships and enduring communications that produce healthy and resilient mindsets.

In particular, individuals who possess adaptive mindsets with a realistic view of ongoing psychosocial stressors, be it from the impact of the pandemic or other influential events, are more likely to benefit when moving forward with life. In other words, the individual in question leverages these experiences as a means of “stress-related growth,” thereby enhancing the overall quality of relationships. Tentative studies in stress management have yielded promising support for interventions that aim to modulate mindsets (as a function of the stress response) by proper appraisal of the stress stimuli, according to Dr. Van Bavel and associates.
 

Employing assessment scales

To mitigate the stress response, clinicians need to use the relevant stress scales for assessing the full impact of distress brought on by COVID-19 and optimizing therapeutic modalities for those who need them most. Again, the stress response would vary, depending on the patient, and may include paranoia, xenophobia, compulsive ritualistic behavior, as well as full-fledged symptoms of acute stress disorder/PTSD.Steven Taylor, PhD, RPsych, and associates, part of a research team funded by the Canadian Institutes of Health Research and the University of Regina (Sask.), formulated their proprietary COVID Stress Scales (CSS) based on 36 items pertaining to individual anxiety and/or stress responses.¹⁰

As general purpose pandemic scales, the assessment tools will be transferable to similar outbreaks, and have been examined for validity and reliability. Additional validation scales include the Patient Health Questionnaire–4 for anxiety and depression, the Short Health Anxiety Inventory for anxiety (irrespective of physical condition), and the Marlowe-Crowne Social Desirability Scale–Short Form for psychological well-being based on the presence (or the lack thereof) of desirable characteristics.¹⁰ As a composite scale and predictive tool (especially with respect to future pandemics), the CSS allows clinicians a means of identifying the people who are most compliant with safety procedures, social distancing, hygiene expectations, and vaccine protocols – when applicable – reported Dr. Taylor and associates.
 

Moving forward: The next step in COVID-19 preparedness

As clinicians continue to develop guidelines that are befitting of COVID-19’s “new normal,” a holistic psychosocial framework will need to integrate the various psychometrics gathered from assessment scales, as well as understanding trauma, especially with respect to the HPA axis.

For starters, there is a certain element of “anticipatory anxiety” for those experiencing distress from COVID-19. A highly uncertain future with no immediate cure in the future, isolation and social estrangement, as well as financial setbacks, compound the situation. Moreover, the DSM fails to acknowledge other sources of traumatic experiences that are systemic in nature, such as discriminatory practices, injustice, and/or persecution.

It has also been noted that some distressed individuals experience a hypervigilant state that is comparable with PTSD.¹¹ There may be a push to incorporate machine learning and other modalities to better identify those at risk (for example, health care professionals who perform their duties with limited resources, thereby inducing sleep dysregulation, anxiety, and hopelessness) for mental health deterioration. Interventions may need to be coordinated in a timely manner to disrupt the progression of acute stress disorder to PTSD. Peer support programs and resiliency training – successful therapeutic approaches for PTSD – may prove to have considerable utility for mitigating the overall stress response of COVID-19.¹²

References

1. “Red Cross offering online course to manage crisis-related stress.” ABC 6 News. kaaltv.com, 2020 Aug 29.

2. Islam FA, Choudhry C. J Psychiatry Psychiatric Disord 2017;1(5): 290-3.

3. Faravelli C et al. World J Psychiatry. 2012 Feb 22;2(1):13-25.

4. Carmassi C et al. Psychiatry Res. 2015 Jan 30;225(1-2):64-9.

5. Pal R. Endocrine. 2020 Apr 28. doi: 10.1007/s12020-020-02325-1.

6. Steenblock C et al. Mol Psychiatry. 2020 May. doi: 10.1038/s41380-020-0758-9.

7. Wang C et al. Int J Environ Res Public Health. 2020 Jan;17(5):1729.

8. Ho CS et al. Ann Acad Med Singap. 2020 Mar 16;49(3):155-60.

9. Van Bavel JJ et al. Nat Hum Behav. 2020 Apr 30. doi: 10.1038/s41562-020-0884-z.

10. Taylor S et al. J Anxiety Disord. 2020 May 4;72:102232.

11. Horesh D, Brown AD. Psychol Trauma. 2020 May;12(4):331-5.

12. Clark H et al. National Health Library and Knowledge Service/Evidence Team. Summary of Evidence: COVID-19, 2020 May 22. Version 2.0.

Dr. Faisal A. Islam is a medical adviser for the International Maternal and Child Health Foundation, Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Mohammed S. Islam is a research physician and extern at Interfaith Medical Center, New York. Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the International Maternal and Child Health Foundation. Dr. Jolayemi is an attending psychiatrist at Interfaith Medical Center. No disclosures were reported.

Psychological First Aid is an innovative program launched by the American Red Cross with the goal of addressing issues of concern such as those stemming from COVID-19–related stress. According to Red Cross mental health volunteer representative Deb Butman-Perkins, the program provides “a general overview of what does stress look like, how do we feel it, how do we recognize it in our bodies ... physical, emotional, spiritual, physiological, where does all that stress occur?”¹

The program brings a spotlight to the interdisciplinary nature of the stress response, especially with respect to the importance of developing the necessary coping skills during an ongoing crisis. However, to effectively evaluate and manage the overall stress response for psychiatric patients during quarantine conditions, as well as those who are formally diagnosed with COVID-19, clinicians also will need to revisit what we’ve learned about the hypothalamic-pituitary-adrenal (HPA) axis.

We know that the stress response – which varies somewhat across the spectrum – is necessary to ensure homeostatic regulation. A feedback loop is initiated at the receptor level, involving a myriad of hormones and chemical signals that bring forth the body’s “flight-or-fight” response. Hormones such as epinephrine/norepinephrine and cortisol are secreted by the HPA axis in reaction to the stress response, resulting in a spike in heart rate, blood pressure, and transient hyperglycemia, respectively. In particular, hyperglycemia provides immediate energy to muscles during a perceived crisis.²

In addition, prolonged exposure to living in quarantine can lead to feelings of isolation and estrangement – and excessive anxiety. Combined, those conditions may exert an indelible effect on the HPA axis – leading to a warped pattern of cortisol secretion with respect to baseline.³ (It has been noted in the literature that serum cortisol plays a protective role in thwarting off the effects of PTSD development. Consistent with this line of thinking, military personnel have been preemptively treated with high-dose cortisol during acute exposure.)

Prolonged exposure to psychosocial stressors also increases the overall risk of developing medical comorbidities. Patients who adopt maladaptive responses to traumatic events, for example, may experience dysregulation in eating behaviors and/or disordered sleep.⁴

In light of those realities, clinicians should explore the role of steroid therapy as a means of treating mental health patients experiencing psychological stress formation tied to ongoing quarantine conditions.
 

Challenges of neuroendocrine medications for COVID-19

COVID-19, caused by exposure to SARS-CoV-2, adeptly leverages the ACE2 receptor of the lungs as an entry point to evade the host’s defenses. It should be noted that the ACE2 protein is expressed on the cells of multiple organs of the body, including the adrenals, which are largely responsible for coordinating the stress response of the HPA axis.

Postmortem analysis from severe acute respiratory syndrome (SARS-CoV is also from the Coronaviridae family) patients indicates the presence of necrotic adrenal cells, further solidifying the association of the HPA axis to the COVID-19 disease state and pathophysiological course.⁵ Molecular mimicry of the adrenocorticotropic hormone allows SARS-CoV the ability to infiltrate the host’s defenses, in particular, the ability to mount a clinically apt cortisol stress response (e.g., hypocortisolism).As for those who survived the 2003 SARS outbreak, less than half of the patients have been observed to develop symptoms of frank hypocortisolism within a few months after exposure.

The World Health Organization recently endorsed the use of steroid therapy for critically ill COVID-19 patients, and an ongoing clinical trial is evaluating the safety and efficacy parameters of corticosteroids in COVID-19–exposed patients.

In addition, there is reason to believe that application of prophylactic steroids might affect the overall clinical course of COVID-19, thereby reducing mortality and morbidity rates in patients with severe presentation, such as septic shock. The rationale for this line of thought is based on the ability of glucocorticoids to suppress an ensuing cytokine storm by the virus in question.^5,6 In clinical practice, steroids have been used to treat a host of viral diseases, including influenza, respiratory syncytial virus, and Middle East respiratory syndrome coronavirus.

Aside from the selective use of corticosteroids, the medication regimen may incorporate ACE inhibitors and/or angiotensin receptor blockers (ARBs) because of COVID-19’s ability to activate the renin-angiotensin-aldosterone system with respect to the physiological stress response.

The interplay of the HPA axis with the sympathoadrenal system is responsible for adaptive behaviors in the individual. Disrupted feedback loops from prolonged activation are associated with numerous stress-based conditions in mental illness, namely, PTSD, anxiety, and mood disorders. We are concerned about frontline health care workers, who are particularly prone to chronic stress and burnout because of the cumbersome patient load and equipment shortage that have characterized the coronavirus crisis.

Timely administration of corticosteroids on a case-by-case basis would keep the cytokines at bay by precluding their undue activation of the HPA axis and corresponding cascade stress response. Steroids are also known to restore disrupted feedback loops at the level of the immune cells. However, because of conflicting reports concerning viral clearance in some SARS and COVID-19 studies, treatment with steroids may be limited to select patient populations with the necessary dose adjustments. Ongoing clinical trials will further elucidate upon the applicability of steroids as well as the role of other neuroendocrine agents, such as ACE inhibitors or ARBs, in the treatment of COVID-19.
 

Behavioral manifestations and psychosocial health

As far as the stress response is concerned, an analysis performed by researchers in China after the COVID-19 outbreak found gender disparities in symptom expression. In the study (n = 1,210) the researchers found in female citizens a greater frequency of behavioral manifestations, including acute stress reaction, and symptoms of anxiety and mood disorders – namely, depression.⁷ Patient perception and awareness of the perils of coronavirus typically varied across the spectrum; some individuals reportedly undermined and devalued their risk of contracting COVID-19 – these patients may benefit from therapeutic modalities, such as cognitive-behavioral therapy (CBT), as a means of challenging their firmly entrenched cognitive distortions. CBT is an effective tool in addressing maladaptive coping responses, because these strategies tend to correspond with poor prognosis with respect to overall mental health. Aside from CBT, the clinician may advise other behavioral techniques, such as relaxation training, with the aim of controlling the symptoms of mood and anxiety disorders.

We often take for granted general pandemic safety precautions, such as maintaining physical distancing coupled with engaging in regular hand hygiene and wearing masks, but these actions also are known to alleviate mental anguish. Access to accurate and easy-to-consume health information regarding COVID-19 is also associated with psychological well-being during the quarantine.⁸

An intriguing “phenomenon” has emerged in the form of “panic buying.”However, researchers reported in the peer-reviewed journal Nature Human Behaviour that this pattern of behaviors is not typical for those under distress and represents an overstated misnomer of sorts. According to Jay J. Van Bavel, PhD, and associates, prevailing reports from news outlets have skewed the features of a panic. “News stories that employ the language of panic often create the very phenomena that they purport to condemn,” Dr. Van Bavel and associates wrote. “They can foster the very individualism and competitiveness that turn sensible preparations into dysfunctional stockpiling and undermine the sense of collective purpose which facilitates people supporting one another during an emergency.”⁹

The researchers proceeded to highlight the scope of effective crisis leadership with respect to establishing a sense of communal “self-efficacy and hope.” The influence of organized leadership serves to solidify the structure of the community as a whole, allowing group members the opportunity to address the stressors of interest. Such leadership may mitigate the stress response by fostering a necessary, healthy set for stress management.

Strategies aimed at supporting mental health

Coping and stress management strategies may include the process of building virtual networks (e.g., social media platforms) because physical distancing may contribute toward further isolation and social estrangement. However, it should be noted that ideally social media consumption should be centered upon interactive enrichment activities that provide a suitable substitute for the absence of physical support systems. The goal is to facilitate meaningful relationships and enduring communications that produce healthy and resilient mindsets.

In particular, individuals who possess adaptive mindsets with a realistic view of ongoing psychosocial stressors, be it from the impact of the pandemic or other influential events, are more likely to benefit when moving forward with life. In other words, the individual in question leverages these experiences as a means of “stress-related growth,” thereby enhancing the overall quality of relationships. Tentative studies in stress management have yielded promising support for interventions that aim to modulate mindsets (as a function of the stress response) by proper appraisal of the stress stimuli, according to Dr. Van Bavel and associates.
 

Employing assessment scales

To mitigate the stress response, clinicians need to use the relevant stress scales for assessing the full impact of distress brought on by COVID-19 and optimizing therapeutic modalities for those who need them most. Again, the stress response would vary, depending on the patient, and may include paranoia, xenophobia, compulsive ritualistic behavior, as well as full-fledged symptoms of acute stress disorder/PTSD.Steven Taylor, PhD, RPsych, and associates, part of a research team funded by the Canadian Institutes of Health Research and the University of Regina (Sask.), formulated their proprietary COVID Stress Scales (CSS) based on 36 items pertaining to individual anxiety and/or stress responses.¹⁰

As general purpose pandemic scales, the assessment tools will be transferable to similar outbreaks, and have been examined for validity and reliability. Additional validation scales include the Patient Health Questionnaire–4 for anxiety and depression, the Short Health Anxiety Inventory for anxiety (irrespective of physical condition), and the Marlowe-Crowne Social Desirability Scale–Short Form for psychological well-being based on the presence (or the lack thereof) of desirable characteristics.¹⁰ As a composite scale and predictive tool (especially with respect to future pandemics), the CSS allows clinicians a means of identifying the people who are most compliant with safety procedures, social distancing, hygiene expectations, and vaccine protocols – when applicable – reported Dr. Taylor and associates.
 

Moving forward: The next step in COVID-19 preparedness

As clinicians continue to develop guidelines that are befitting of COVID-19’s “new normal,” a holistic psychosocial framework will need to integrate the various psychometrics gathered from assessment scales, as well as understanding trauma, especially with respect to the HPA axis.

For starters, there is a certain element of “anticipatory anxiety” for those experiencing distress from COVID-19. A highly uncertain future with no immediate cure in the future, isolation and social estrangement, as well as financial setbacks, compound the situation. Moreover, the DSM fails to acknowledge other sources of traumatic experiences that are systemic in nature, such as discriminatory practices, injustice, and/or persecution.

It has also been noted that some distressed individuals experience a hypervigilant state that is comparable with PTSD.¹¹ There may be a push to incorporate machine learning and other modalities to better identify those at risk (for example, health care professionals who perform their duties with limited resources, thereby inducing sleep dysregulation, anxiety, and hopelessness) for mental health deterioration. Interventions may need to be coordinated in a timely manner to disrupt the progression of acute stress disorder to PTSD. Peer support programs and resiliency training – successful therapeutic approaches for PTSD – may prove to have considerable utility for mitigating the overall stress response of COVID-19.¹²

References

1. “Red Cross offering online course to manage crisis-related stress.” ABC 6 News. kaaltv.com, 2020 Aug 29.

2. Islam FA, Choudhry C. J Psychiatry Psychiatric Disord 2017;1(5): 290-3.

3. Faravelli C et al. World J Psychiatry. 2012 Feb 22;2(1):13-25.

4. Carmassi C et al. Psychiatry Res. 2015 Jan 30;225(1-2):64-9.

5. Pal R. Endocrine. 2020 Apr 28. doi: 10.1007/s12020-020-02325-1.

6. Steenblock C et al. Mol Psychiatry. 2020 May. doi: 10.1038/s41380-020-0758-9.

7. Wang C et al. Int J Environ Res Public Health. 2020 Jan;17(5):1729.

8. Ho CS et al. Ann Acad Med Singap. 2020 Mar 16;49(3):155-60.

9. Van Bavel JJ et al. Nat Hum Behav. 2020 Apr 30. doi: 10.1038/s41562-020-0884-z.

10. Taylor S et al. J Anxiety Disord. 2020 May 4;72:102232.

11. Horesh D, Brown AD. Psychol Trauma. 2020 May;12(4):331-5.

12. Clark H et al. National Health Library and Knowledge Service/Evidence Team. Summary of Evidence: COVID-19, 2020 May 22. Version 2.0.

Dr. Faisal A. Islam is a medical adviser for the International Maternal and Child Health Foundation, Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Mohammed S. Islam is a research physician and extern at Interfaith Medical Center, New York. Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the International Maternal and Child Health Foundation. Dr. Jolayemi is an attending psychiatrist at Interfaith Medical Center. No disclosures were reported.

Psychological First Aid is an innovative program launched by the American Red Cross with the goal of addressing issues of concern such as those stemming from COVID-19–related stress. According to Red Cross mental health volunteer representative Deb Butman-Perkins, the program provides “a general overview of what does stress look like, how do we feel it, how do we recognize it in our bodies ... physical, emotional, spiritual, physiological, where does all that stress occur?”¹

The program brings a spotlight to the interdisciplinary nature of the stress response, especially with respect to the importance of developing the necessary coping skills during an ongoing crisis. However, to effectively evaluate and manage the overall stress response for psychiatric patients during quarantine conditions, as well as those who are formally diagnosed with COVID-19, clinicians also will need to revisit what we’ve learned about the hypothalamic-pituitary-adrenal (HPA) axis.

We know that the stress response – which varies somewhat across the spectrum – is necessary to ensure homeostatic regulation. A feedback loop is initiated at the receptor level, involving a myriad of hormones and chemical signals that bring forth the body’s “flight-or-fight” response. Hormones such as epinephrine/norepinephrine and cortisol are secreted by the HPA axis in reaction to the stress response, resulting in a spike in heart rate, blood pressure, and transient hyperglycemia, respectively. In particular, hyperglycemia provides immediate energy to muscles during a perceived crisis.²

In addition, prolonged exposure to living in quarantine can lead to feelings of isolation and estrangement – and excessive anxiety. Combined, those conditions may exert an indelible effect on the HPA axis – leading to a warped pattern of cortisol secretion with respect to baseline.³ (It has been noted in the literature that serum cortisol plays a protective role in thwarting off the effects of PTSD development. Consistent with this line of thinking, military personnel have been preemptively treated with high-dose cortisol during acute exposure.)

Prolonged exposure to psychosocial stressors also increases the overall risk of developing medical comorbidities. Patients who adopt maladaptive responses to traumatic events, for example, may experience dysregulation in eating behaviors and/or disordered sleep.⁴

In light of those realities, clinicians should explore the role of steroid therapy as a means of treating mental health patients experiencing psychological stress formation tied to ongoing quarantine conditions.
 

Challenges of neuroendocrine medications for COVID-19

COVID-19, caused by exposure to SARS-CoV-2, adeptly leverages the ACE2 receptor of the lungs as an entry point to evade the host’s defenses. It should be noted that the ACE2 protein is expressed on the cells of multiple organs of the body, including the adrenals, which are largely responsible for coordinating the stress response of the HPA axis.

Postmortem analysis from severe acute respiratory syndrome (SARS-CoV is also from the Coronaviridae family) patients indicates the presence of necrotic adrenal cells, further solidifying the association of the HPA axis to the COVID-19 disease state and pathophysiological course.⁵ Molecular mimicry of the adrenocorticotropic hormone allows SARS-CoV the ability to infiltrate the host’s defenses, in particular, the ability to mount a clinically apt cortisol stress response (e.g., hypocortisolism).As for those who survived the 2003 SARS outbreak, less than half of the patients have been observed to develop symptoms of frank hypocortisolism within a few months after exposure.

The World Health Organization recently endorsed the use of steroid therapy for critically ill COVID-19 patients, and an ongoing clinical trial is evaluating the safety and efficacy parameters of corticosteroids in COVID-19–exposed patients.

In addition, there is reason to believe that application of prophylactic steroids might affect the overall clinical course of COVID-19, thereby reducing mortality and morbidity rates in patients with severe presentation, such as septic shock. The rationale for this line of thought is based on the ability of glucocorticoids to suppress an ensuing cytokine storm by the virus in question.^5,6 In clinical practice, steroids have been used to treat a host of viral diseases, including influenza, respiratory syncytial virus, and Middle East respiratory syndrome coronavirus.

Aside from the selective use of corticosteroids, the medication regimen may incorporate ACE inhibitors and/or angiotensin receptor blockers (ARBs) because of COVID-19’s ability to activate the renin-angiotensin-aldosterone system with respect to the physiological stress response.

The interplay of the HPA axis with the sympathoadrenal system is responsible for adaptive behaviors in the individual. Disrupted feedback loops from prolonged activation are associated with numerous stress-based conditions in mental illness, namely, PTSD, anxiety, and mood disorders. We are concerned about frontline health care workers, who are particularly prone to chronic stress and burnout because of the cumbersome patient load and equipment shortage that have characterized the coronavirus crisis.

Timely administration of corticosteroids on a case-by-case basis would keep the cytokines at bay by precluding their undue activation of the HPA axis and corresponding cascade stress response. Steroids are also known to restore disrupted feedback loops at the level of the immune cells. However, because of conflicting reports concerning viral clearance in some SARS and COVID-19 studies, treatment with steroids may be limited to select patient populations with the necessary dose adjustments. Ongoing clinical trials will further elucidate upon the applicability of steroids as well as the role of other neuroendocrine agents, such as ACE inhibitors or ARBs, in the treatment of COVID-19.
 

Behavioral manifestations and psychosocial health

As far as the stress response is concerned, an analysis performed by researchers in China after the COVID-19 outbreak found gender disparities in symptom expression. In the study (n = 1,210) the researchers found in female citizens a greater frequency of behavioral manifestations, including acute stress reaction, and symptoms of anxiety and mood disorders – namely, depression.⁷ Patient perception and awareness of the perils of coronavirus typically varied across the spectrum; some individuals reportedly undermined and devalued their risk of contracting COVID-19 – these patients may benefit from therapeutic modalities, such as cognitive-behavioral therapy (CBT), as a means of challenging their firmly entrenched cognitive distortions. CBT is an effective tool in addressing maladaptive coping responses, because these strategies tend to correspond with poor prognosis with respect to overall mental health. Aside from CBT, the clinician may advise other behavioral techniques, such as relaxation training, with the aim of controlling the symptoms of mood and anxiety disorders.

We often take for granted general pandemic safety precautions, such as maintaining physical distancing coupled with engaging in regular hand hygiene and wearing masks, but these actions also are known to alleviate mental anguish. Access to accurate and easy-to-consume health information regarding COVID-19 is also associated with psychological well-being during the quarantine.⁸

An intriguing “phenomenon” has emerged in the form of “panic buying.”However, researchers reported in the peer-reviewed journal Nature Human Behaviour that this pattern of behaviors is not typical for those under distress and represents an overstated misnomer of sorts. According to Jay J. Van Bavel, PhD, and associates, prevailing reports from news outlets have skewed the features of a panic. “News stories that employ the language of panic often create the very phenomena that they purport to condemn,” Dr. Van Bavel and associates wrote. “They can foster the very individualism and competitiveness that turn sensible preparations into dysfunctional stockpiling and undermine the sense of collective purpose which facilitates people supporting one another during an emergency.”⁹

The researchers proceeded to highlight the scope of effective crisis leadership with respect to establishing a sense of communal “self-efficacy and hope.” The influence of organized leadership serves to solidify the structure of the community as a whole, allowing group members the opportunity to address the stressors of interest. Such leadership may mitigate the stress response by fostering a necessary, healthy set for stress management.

Strategies aimed at supporting mental health

Coping and stress management strategies may include the process of building virtual networks (e.g., social media platforms) because physical distancing may contribute toward further isolation and social estrangement. However, it should be noted that ideally social media consumption should be centered upon interactive enrichment activities that provide a suitable substitute for the absence of physical support systems. The goal is to facilitate meaningful relationships and enduring communications that produce healthy and resilient mindsets.

In particular, individuals who possess adaptive mindsets with a realistic view of ongoing psychosocial stressors, be it from the impact of the pandemic or other influential events, are more likely to benefit when moving forward with life. In other words, the individual in question leverages these experiences as a means of “stress-related growth,” thereby enhancing the overall quality of relationships. Tentative studies in stress management have yielded promising support for interventions that aim to modulate mindsets (as a function of the stress response) by proper appraisal of the stress stimuli, according to Dr. Van Bavel and associates.
 

Employing assessment scales

To mitigate the stress response, clinicians need to use the relevant stress scales for assessing the full impact of distress brought on by COVID-19 and optimizing therapeutic modalities for those who need them most. Again, the stress response would vary, depending on the patient, and may include paranoia, xenophobia, compulsive ritualistic behavior, as well as full-fledged symptoms of acute stress disorder/PTSD.Steven Taylor, PhD, RPsych, and associates, part of a research team funded by the Canadian Institutes of Health Research and the University of Regina (Sask.), formulated their proprietary COVID Stress Scales (CSS) based on 36 items pertaining to individual anxiety and/or stress responses.¹⁰

As general purpose pandemic scales, the assessment tools will be transferable to similar outbreaks, and have been examined for validity and reliability. Additional validation scales include the Patient Health Questionnaire–4 for anxiety and depression, the Short Health Anxiety Inventory for anxiety (irrespective of physical condition), and the Marlowe-Crowne Social Desirability Scale–Short Form for psychological well-being based on the presence (or the lack thereof) of desirable characteristics.¹⁰ As a composite scale and predictive tool (especially with respect to future pandemics), the CSS allows clinicians a means of identifying the people who are most compliant with safety procedures, social distancing, hygiene expectations, and vaccine protocols – when applicable – reported Dr. Taylor and associates.
 

Moving forward: The next step in COVID-19 preparedness

As clinicians continue to develop guidelines that are befitting of COVID-19’s “new normal,” a holistic psychosocial framework will need to integrate the various psychometrics gathered from assessment scales, as well as understanding trauma, especially with respect to the HPA axis.

For starters, there is a certain element of “anticipatory anxiety” for those experiencing distress from COVID-19. A highly uncertain future with no immediate cure in the future, isolation and social estrangement, as well as financial setbacks, compound the situation. Moreover, the DSM fails to acknowledge other sources of traumatic experiences that are systemic in nature, such as discriminatory practices, injustice, and/or persecution.

It has also been noted that some distressed individuals experience a hypervigilant state that is comparable with PTSD.¹¹ There may be a push to incorporate machine learning and other modalities to better identify those at risk (for example, health care professionals who perform their duties with limited resources, thereby inducing sleep dysregulation, anxiety, and hopelessness) for mental health deterioration. Interventions may need to be coordinated in a timely manner to disrupt the progression of acute stress disorder to PTSD. Peer support programs and resiliency training – successful therapeutic approaches for PTSD – may prove to have considerable utility for mitigating the overall stress response of COVID-19.¹²

References

1. “Red Cross offering online course to manage crisis-related stress.” ABC 6 News. kaaltv.com, 2020 Aug 29.

2. Islam FA, Choudhry C. J Psychiatry Psychiatric Disord 2017;1(5): 290-3.

3. Faravelli C et al. World J Psychiatry. 2012 Feb 22;2(1):13-25.

4. Carmassi C et al. Psychiatry Res. 2015 Jan 30;225(1-2):64-9.

5. Pal R. Endocrine. 2020 Apr 28. doi: 10.1007/s12020-020-02325-1.

6. Steenblock C et al. Mol Psychiatry. 2020 May. doi: 10.1038/s41380-020-0758-9.

7. Wang C et al. Int J Environ Res Public Health. 2020 Jan;17(5):1729.

8. Ho CS et al. Ann Acad Med Singap. 2020 Mar 16;49(3):155-60.

9. Van Bavel JJ et al. Nat Hum Behav. 2020 Apr 30. doi: 10.1038/s41562-020-0884-z.

10. Taylor S et al. J Anxiety Disord. 2020 May 4;72:102232.

11. Horesh D, Brown AD. Psychol Trauma. 2020 May;12(4):331-5.

12. Clark H et al. National Health Library and Knowledge Service/Evidence Team. Summary of Evidence: COVID-19, 2020 May 22. Version 2.0.

Dr. Faisal A. Islam is a medical adviser for the International Maternal and Child Health Foundation, Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Mohammed S. Islam is a research physician and extern at Interfaith Medical Center, New York. Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the International Maternal and Child Health Foundation. Dr. Jolayemi is an attending psychiatrist at Interfaith Medical Center. No disclosures were reported.

The two top developments of the year in the field of neurostimulation involve the oldest form of the therapy: electroconvulsive therapy, Alexander Sartorius, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

Bram Janssens/Thinkstock

One of these studies shot down the longstanding notion that ECT causes brain damage. The other, a Danish national registry study, demonstrated that ECT is associated with lower all-cause mortality than in patients with similarly severe depression who don’t undergo ECT.

“The take-home messages are that ECT does not lead to brain damage but rather to a profound gray matter increase. And secondly, ECT lowers all-cause mortality in patients with depression,” said Dr. Sartorius, a psychiatrist at the Central Institute of Mental Health in Mannheim, Germany.

The year has been less fruitful in terms of research involving deep brain stimulation using implantable electrodes, he continued.

“Basically, one can state that there is no breaking news in the field of deep brain stimulation. DBS remains a highly experimental form of therapy,” Dr. Sartorius said.
 

ECT-induced brain changes

Investigators participating in the international multicenter Global ECT-MRI Research Collaboration (GEMRIC) reported on the longitudinal effects of ECT on gray matter, white matter, and ventricular volumes in 328 patients who underwent imaging before and after ECT for a major depressive episode, as well as in 95 nondepressed controls.

The key finding was that ECT induced a widespread, nonspecific global increase in gray matter volume. Indeed, the volumetric increase was documented in 79 of 84 gray matter regions of interest. Subcortical gray matter volume increased by a mean of 1.47% in ECT-treated patients, and total cortical volume rose by 1.04%. Total white matter volume remained unchanged.

“The gray matter increase induced by ECT looks quite similar to the gray matter increase seen with physical activity,” Dr. Sartorius noted.

The size of the gray matter volume increase rose with the number of ECT sessions. However, gray matter enlargement in response to ECT showed no relationship with clinical response, indicating that this finding on brain imaging doesn’t have a promising future as a potential biomarker of treatment effectiveness (Biol Psychiatry. 2020 Mar 1;87[5]:451-61).

“The good news from this study is there is no gray matter decrease,” Dr. Sartorius said. “This study enhances the existing evidence falsifying the old idea or dogma that ECT induces brain damage. I would claim that the opposite is clearly the case.”
 

ECT and mortality

The same group of investigators at the University of Copenhagen who several years ago harnessed Danish national patient registries data to report that ECT was associated with an unadjusted 32% and adjusted 23% reduction in the risk of developing dementia in patients aged 70 years and older (Lancet Psychiatry. 2018 Apr;5[4]:348-56) have recently concluded that ECT was also associated with a 19% reduction in all-cause mortality, compared with that of patients hospitalized for major depression who didn’t receive ECT.

The national registries study included 5,004 patients who were treated with ECT and nearly 88,000 others who were hospitalized for major depression during 2005-2016 but didn’t receive ECT. During up to 11.3 years of follow-up, the risk of all-cause mortality was 8% lower with ECT than with no ECT in patients categorized as having mild depression, 17% lower with a history of ECT for moderate depression, 4% less with severe depression without psychotic features, and 30% less with ECT than no ECT for severe depression with psychotic features (J Psychopharmacol. 2020 Mar;34[3]:273-9).

ECT was associated with an adjusted 6.99-fold increased risk of suicide in patients with mild depression. At first look that’s unsettling, Dr. Sartorius said, but he pointed out that the size of the ECT-associated suicide risk lessened with increasing severity of depression, and in fact, there was no increased suicide risk with ECT in severely depressed patients with psychotic features. ECT was also associated with significantly higher rates of psychiatric rehospitalization, emergency department visits, and suicidal behavior in patients classified as having mild or moderate depression. Dr. Sartorius suspects these findings reflect diagnostic uncertainty surrounding the milder forms of depression, coupled with the reality that ECT is generally reserved for the most unstable, treatment-resistant patients.

Deep transcranial magnetic stimulation

A Taiwanese meta-analysis has helped clarify the role of deep transcranial magnetic stimulation (dTMS) for treatment-resistant depression. The meta-analysis included 198 patients with treatment-resistant depression who underwent dTMS and 219 who received sham treatment in a total of 15 studies, only three of which were randomized controlled trials.

Active treatment was associated with a 2.06-fold increased likelihood of remission of depressive symptoms; however, the effect was statistically significant only in the subgroup of patients on concurrent antidepressant medication. Moreover, the therapeutic benefit of dTMS was significantly greater in the nonrandomized studies, where the odds ratio for remission was 3.8-fold greater than with sham therapy. In contrast, the odds ratio for remission with dTMS dropped to 1.37 in the randomized trials (Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109850. doi: 10.1016/j.pnpbp.2019.109850). “dTMS has quite a bit of antidepressant potential in treatment-resistant depression, but as an augmentation strategy. More randomized trials are needed, with a particular focus on which classes of antidepressants might be most effective as concurrent therapy,” Dr. Sartorius concluded.

He reported having no financial conflicts regarding his presentation.

[email protected]

SOURCE: Sartorius A. ECNP 2020, Session TP.03.

The two top developments of the year in the field of neurostimulation involve the oldest form of the therapy: electroconvulsive therapy, Alexander Sartorius, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

Bram Janssens/Thinkstock

One of these studies shot down the longstanding notion that ECT causes brain damage. The other, a Danish national registry study, demonstrated that ECT is associated with lower all-cause mortality than in patients with similarly severe depression who don’t undergo ECT.

“The take-home messages are that ECT does not lead to brain damage but rather to a profound gray matter increase. And secondly, ECT lowers all-cause mortality in patients with depression,” said Dr. Sartorius, a psychiatrist at the Central Institute of Mental Health in Mannheim, Germany.

The year has been less fruitful in terms of research involving deep brain stimulation using implantable electrodes, he continued.

“Basically, one can state that there is no breaking news in the field of deep brain stimulation. DBS remains a highly experimental form of therapy,” Dr. Sartorius said.
 

ECT-induced brain changes

Investigators participating in the international multicenter Global ECT-MRI Research Collaboration (GEMRIC) reported on the longitudinal effects of ECT on gray matter, white matter, and ventricular volumes in 328 patients who underwent imaging before and after ECT for a major depressive episode, as well as in 95 nondepressed controls.

The key finding was that ECT induced a widespread, nonspecific global increase in gray matter volume. Indeed, the volumetric increase was documented in 79 of 84 gray matter regions of interest. Subcortical gray matter volume increased by a mean of 1.47% in ECT-treated patients, and total cortical volume rose by 1.04%. Total white matter volume remained unchanged.

“The gray matter increase induced by ECT looks quite similar to the gray matter increase seen with physical activity,” Dr. Sartorius noted.

The size of the gray matter volume increase rose with the number of ECT sessions. However, gray matter enlargement in response to ECT showed no relationship with clinical response, indicating that this finding on brain imaging doesn’t have a promising future as a potential biomarker of treatment effectiveness (Biol Psychiatry. 2020 Mar 1;87[5]:451-61).

“The good news from this study is there is no gray matter decrease,” Dr. Sartorius said. “This study enhances the existing evidence falsifying the old idea or dogma that ECT induces brain damage. I would claim that the opposite is clearly the case.”
 

ECT and mortality

The same group of investigators at the University of Copenhagen who several years ago harnessed Danish national patient registries data to report that ECT was associated with an unadjusted 32% and adjusted 23% reduction in the risk of developing dementia in patients aged 70 years and older (Lancet Psychiatry. 2018 Apr;5[4]:348-56) have recently concluded that ECT was also associated with a 19% reduction in all-cause mortality, compared with that of patients hospitalized for major depression who didn’t receive ECT.

The national registries study included 5,004 patients who were treated with ECT and nearly 88,000 others who were hospitalized for major depression during 2005-2016 but didn’t receive ECT. During up to 11.3 years of follow-up, the risk of all-cause mortality was 8% lower with ECT than with no ECT in patients categorized as having mild depression, 17% lower with a history of ECT for moderate depression, 4% less with severe depression without psychotic features, and 30% less with ECT than no ECT for severe depression with psychotic features (J Psychopharmacol. 2020 Mar;34[3]:273-9).

ECT was associated with an adjusted 6.99-fold increased risk of suicide in patients with mild depression. At first look that’s unsettling, Dr. Sartorius said, but he pointed out that the size of the ECT-associated suicide risk lessened with increasing severity of depression, and in fact, there was no increased suicide risk with ECT in severely depressed patients with psychotic features. ECT was also associated with significantly higher rates of psychiatric rehospitalization, emergency department visits, and suicidal behavior in patients classified as having mild or moderate depression. Dr. Sartorius suspects these findings reflect diagnostic uncertainty surrounding the milder forms of depression, coupled with the reality that ECT is generally reserved for the most unstable, treatment-resistant patients.

Deep transcranial magnetic stimulation

A Taiwanese meta-analysis has helped clarify the role of deep transcranial magnetic stimulation (dTMS) for treatment-resistant depression. The meta-analysis included 198 patients with treatment-resistant depression who underwent dTMS and 219 who received sham treatment in a total of 15 studies, only three of which were randomized controlled trials.

Active treatment was associated with a 2.06-fold increased likelihood of remission of depressive symptoms; however, the effect was statistically significant only in the subgroup of patients on concurrent antidepressant medication. Moreover, the therapeutic benefit of dTMS was significantly greater in the nonrandomized studies, where the odds ratio for remission was 3.8-fold greater than with sham therapy. In contrast, the odds ratio for remission with dTMS dropped to 1.37 in the randomized trials (Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109850. doi: 10.1016/j.pnpbp.2019.109850). “dTMS has quite a bit of antidepressant potential in treatment-resistant depression, but as an augmentation strategy. More randomized trials are needed, with a particular focus on which classes of antidepressants might be most effective as concurrent therapy,” Dr. Sartorius concluded.

He reported having no financial conflicts regarding his presentation.

[email protected]

SOURCE: Sartorius A. ECNP 2020, Session TP.03.

The two top developments of the year in the field of neurostimulation involve the oldest form of the therapy: electroconvulsive therapy, Alexander Sartorius, MD, said at the virtual congress of the European College of Neuropsychopharmacology.

Bram Janssens/Thinkstock

One of these studies shot down the longstanding notion that ECT causes brain damage. The other, a Danish national registry study, demonstrated that ECT is associated with lower all-cause mortality than in patients with similarly severe depression who don’t undergo ECT.

“The take-home messages are that ECT does not lead to brain damage but rather to a profound gray matter increase. And secondly, ECT lowers all-cause mortality in patients with depression,” said Dr. Sartorius, a psychiatrist at the Central Institute of Mental Health in Mannheim, Germany.

The year has been less fruitful in terms of research involving deep brain stimulation using implantable electrodes, he continued.

“Basically, one can state that there is no breaking news in the field of deep brain stimulation. DBS remains a highly experimental form of therapy,” Dr. Sartorius said.
 

ECT-induced brain changes

Investigators participating in the international multicenter Global ECT-MRI Research Collaboration (GEMRIC) reported on the longitudinal effects of ECT on gray matter, white matter, and ventricular volumes in 328 patients who underwent imaging before and after ECT for a major depressive episode, as well as in 95 nondepressed controls.

The key finding was that ECT induced a widespread, nonspecific global increase in gray matter volume. Indeed, the volumetric increase was documented in 79 of 84 gray matter regions of interest. Subcortical gray matter volume increased by a mean of 1.47% in ECT-treated patients, and total cortical volume rose by 1.04%. Total white matter volume remained unchanged.

“The gray matter increase induced by ECT looks quite similar to the gray matter increase seen with physical activity,” Dr. Sartorius noted.

The size of the gray matter volume increase rose with the number of ECT sessions. However, gray matter enlargement in response to ECT showed no relationship with clinical response, indicating that this finding on brain imaging doesn’t have a promising future as a potential biomarker of treatment effectiveness (Biol Psychiatry. 2020 Mar 1;87[5]:451-61).

“The good news from this study is there is no gray matter decrease,” Dr. Sartorius said. “This study enhances the existing evidence falsifying the old idea or dogma that ECT induces brain damage. I would claim that the opposite is clearly the case.”
 

ECT and mortality

The same group of investigators at the University of Copenhagen who several years ago harnessed Danish national patient registries data to report that ECT was associated with an unadjusted 32% and adjusted 23% reduction in the risk of developing dementia in patients aged 70 years and older (Lancet Psychiatry. 2018 Apr;5[4]:348-56) have recently concluded that ECT was also associated with a 19% reduction in all-cause mortality, compared with that of patients hospitalized for major depression who didn’t receive ECT.

The national registries study included 5,004 patients who were treated with ECT and nearly 88,000 others who were hospitalized for major depression during 2005-2016 but didn’t receive ECT. During up to 11.3 years of follow-up, the risk of all-cause mortality was 8% lower with ECT than with no ECT in patients categorized as having mild depression, 17% lower with a history of ECT for moderate depression, 4% less with severe depression without psychotic features, and 30% less with ECT than no ECT for severe depression with psychotic features (J Psychopharmacol. 2020 Mar;34[3]:273-9).

ECT was associated with an adjusted 6.99-fold increased risk of suicide in patients with mild depression. At first look that’s unsettling, Dr. Sartorius said, but he pointed out that the size of the ECT-associated suicide risk lessened with increasing severity of depression, and in fact, there was no increased suicide risk with ECT in severely depressed patients with psychotic features. ECT was also associated with significantly higher rates of psychiatric rehospitalization, emergency department visits, and suicidal behavior in patients classified as having mild or moderate depression. Dr. Sartorius suspects these findings reflect diagnostic uncertainty surrounding the milder forms of depression, coupled with the reality that ECT is generally reserved for the most unstable, treatment-resistant patients.

Deep transcranial magnetic stimulation

A Taiwanese meta-analysis has helped clarify the role of deep transcranial magnetic stimulation (dTMS) for treatment-resistant depression. The meta-analysis included 198 patients with treatment-resistant depression who underwent dTMS and 219 who received sham treatment in a total of 15 studies, only three of which were randomized controlled trials.

Active treatment was associated with a 2.06-fold increased likelihood of remission of depressive symptoms; however, the effect was statistically significant only in the subgroup of patients on concurrent antidepressant medication. Moreover, the therapeutic benefit of dTMS was significantly greater in the nonrandomized studies, where the odds ratio for remission was 3.8-fold greater than with sham therapy. In contrast, the odds ratio for remission with dTMS dropped to 1.37 in the randomized trials (Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109850. doi: 10.1016/j.pnpbp.2019.109850). “dTMS has quite a bit of antidepressant potential in treatment-resistant depression, but as an augmentation strategy. More randomized trials are needed, with a particular focus on which classes of antidepressants might be most effective as concurrent therapy,” Dr. Sartorius concluded.

He reported having no financial conflicts regarding his presentation.

[email protected]

SOURCE: Sartorius A. ECNP 2020, Session TP.03.

The patients walk into Dr. Melissa Marshall’s community clinics in Northern California with the telltale symptoms. They’re having trouble breathing. It may even hurt to inhale. They’ve got a cough, and the sore throat is definitely there.

A straight case of COVID-19? Not so fast. This is wildfire country.

Up and down the West Coast, hospitals and health facilities are reporting an influx of patients with problems most likely related to smoke inhalation. As fires rage largely uncontrolled amid dry heat and high winds, smoke and ash are billowing and settling on coastal areas like San Francisco and cities and towns hundreds of miles inland as well, turning the sky orange or gray and making even ordinary breathing difficult.

But that, Marshall said, is only part of the challenge. Facilities already strapped for testing supplies and personal protective equipment must first rule out COVID-19 in these patients, because many of the symptoms they present with are the same as those caused by the virus.

“Obviously, there’s overlap in the symptoms,” said Marshall, the CEO of CommuniCare, a collection of six clinics in Yolo County, near Sacramento, that treats mostly underinsured and uninsured patients. “Any time someone comes in with even some of those symptoms, we ask ourselves, ‘Is it COVID?’ At the end of the day, clinically speaking, I still want to rule out the virus.”

The protocol is to treat the symptoms, whatever their cause, while recommending that the patient quarantine until test results for the virus come back, she said.

It is a scene playing out in numerous hospitals. Administrators and physicians, finely attuned to COVID-19’s ability to spread quickly and wreak havoc, simply won’t take a chance when they recognize symptoms that could emanate from the virus.

“We’ve seen an increase in patients presenting to the emergency department with respiratory distress,” said Dr. Nanette Mickiewicz, president and CEO of Dominican Hospital in Santa Cruz. “As this can also be a symptom of COVID-19, we’re treating these patients as we would any person under investigation for coronavirus until we can rule them out through our screening process.” During the workup, symptoms that are more specific to COVID-19, like fever, would become apparent.

For the workers at Dominican, the issue moved to the top of the list quickly. Santa Cruz and San Mateo counties have borne the brunt of the CZU Lightning Complex fires, which as of Sept. 10 had burned more than 86,000 acres, destroying 1,100 structures and threatening more than 7,600 others. Nearly a month after they began, the fires were approximately 84% contained, but thousands of people remained evacuated.

Dominican, a Dignity Health hospital, is “open, safe and providing care,” Mickiewicz said. Multiple tents erected outside the building serve as an extension of its ER waiting room. They also are used to perform what has come to be understood as an essential role: separating those with symptoms of COVID-19 from those without.

At the two Solano County hospitals operated by NorthBay Healthcare, the path of some of the wildfires prompted officials to review their evacuation procedures, said spokesperson Steve Huddleston. They ultimately avoided the need to evacuate patients, and new ones arrived with COVID-like symptoms that may actually have been from smoke inhalation.

Huddleston said NorthBay’s intake process “calls for anyone with COVID characteristics to be handled as [a] patient under investigation for COVID, which means they’re separated, screened and managed by staff in special PPE.” At the two hospitals, which have handled nearly 200 COVID cases so far, the protocol is well established.

Hospitals in California, though not under siege in most cases, are dealing with multiple issues they might typically face only sporadically. In Napa County, Adventist Health St. Helena Hospital evacuated 51 patients on a single August night as a fire approached, moving them to 10 other facilities according to their needs and bed space. After a 10-day closure, the hospital was allowed to reopen as evacuation orders were lifted, the fire having been contained some distance away.

The wildfires are also taking a personal toll on health care workers. CommuniCare’s Marshall lost her family’s home in rural Winters, along with 20 acres of olive trees and other plantings that surrounded it, in the Aug. 19 fires that swept through Solano County.

“They called it a ‘firenado,’ ” Marshall said. An apparent confluence of three fires raged out of control, demolishing thousands of acres. With her family safely accounted for and temporary housing arranged by a friend, she returned to work. “Our clinics interact with a very vulnerable population,” she said, “and this is a critical time for them.”

While she pondered how her family would rebuild, the CEO was faced with another immediate crisis: the clinic’s shortage of supplies. Last month, CommuniCare got down to 19 COVID test kits on hand, and ran so low on swabs “that we were literally turning to our veterinary friends for reinforcements,” the doctor said. The clinic’s COVID test results, meanwhile, were taking nearly two weeks to be returned from an overwhelmed outside lab, rendering contact tracing almost useless.

Those situations have been addressed, at least temporarily, Marshall said. But although the West Coast is in the most dangerous time of year for wildfires, generally September to December, another complication for health providers lies on the horizon: flu season.

The Southern Hemisphere, whose influenza trends during our summer months typically predict what’s to come for the U.S., has had very little of the disease this year, presumably because of restricted travel, social distancing and face masks. But it’s too early to be sure what the U.S. flu season will entail.

“You can start to see some cases of the flu in late October,” said Marshall, “and the reality is that it’s going to carry a number of characteristics that could also be symptomatic of COVID. And nothing changes: You have to rule it out, just to eliminate the risk.”

KHN (Kaiser Health News) is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente. This KHN story first published on California Healthline, a service of the California Health Care Foundation.

The patients walk into Dr. Melissa Marshall’s community clinics in Northern California with the telltale symptoms. They’re having trouble breathing. It may even hurt to inhale. They’ve got a cough, and the sore throat is definitely there.

A straight case of COVID-19? Not so fast. This is wildfire country.

Up and down the West Coast, hospitals and health facilities are reporting an influx of patients with problems most likely related to smoke inhalation. As fires rage largely uncontrolled amid dry heat and high winds, smoke and ash are billowing and settling on coastal areas like San Francisco and cities and towns hundreds of miles inland as well, turning the sky orange or gray and making even ordinary breathing difficult.

But that, Marshall said, is only part of the challenge. Facilities already strapped for testing supplies and personal protective equipment must first rule out COVID-19 in these patients, because many of the symptoms they present with are the same as those caused by the virus.

“Obviously, there’s overlap in the symptoms,” said Marshall, the CEO of CommuniCare, a collection of six clinics in Yolo County, near Sacramento, that treats mostly underinsured and uninsured patients. “Any time someone comes in with even some of those symptoms, we ask ourselves, ‘Is it COVID?’ At the end of the day, clinically speaking, I still want to rule out the virus.”

The protocol is to treat the symptoms, whatever their cause, while recommending that the patient quarantine until test results for the virus come back, she said.

It is a scene playing out in numerous hospitals. Administrators and physicians, finely attuned to COVID-19’s ability to spread quickly and wreak havoc, simply won’t take a chance when they recognize symptoms that could emanate from the virus.

“We’ve seen an increase in patients presenting to the emergency department with respiratory distress,” said Dr. Nanette Mickiewicz, president and CEO of Dominican Hospital in Santa Cruz. “As this can also be a symptom of COVID-19, we’re treating these patients as we would any person under investigation for coronavirus until we can rule them out through our screening process.” During the workup, symptoms that are more specific to COVID-19, like fever, would become apparent.

For the workers at Dominican, the issue moved to the top of the list quickly. Santa Cruz and San Mateo counties have borne the brunt of the CZU Lightning Complex fires, which as of Sept. 10 had burned more than 86,000 acres, destroying 1,100 structures and threatening more than 7,600 others. Nearly a month after they began, the fires were approximately 84% contained, but thousands of people remained evacuated.

Dominican, a Dignity Health hospital, is “open, safe and providing care,” Mickiewicz said. Multiple tents erected outside the building serve as an extension of its ER waiting room. They also are used to perform what has come to be understood as an essential role: separating those with symptoms of COVID-19 from those without.

At the two Solano County hospitals operated by NorthBay Healthcare, the path of some of the wildfires prompted officials to review their evacuation procedures, said spokesperson Steve Huddleston. They ultimately avoided the need to evacuate patients, and new ones arrived with COVID-like symptoms that may actually have been from smoke inhalation.

Huddleston said NorthBay’s intake process “calls for anyone with COVID characteristics to be handled as [a] patient under investigation for COVID, which means they’re separated, screened and managed by staff in special PPE.” At the two hospitals, which have handled nearly 200 COVID cases so far, the protocol is well established.

Hospitals in California, though not under siege in most cases, are dealing with multiple issues they might typically face only sporadically. In Napa County, Adventist Health St. Helena Hospital evacuated 51 patients on a single August night as a fire approached, moving them to 10 other facilities according to their needs and bed space. After a 10-day closure, the hospital was allowed to reopen as evacuation orders were lifted, the fire having been contained some distance away.

The wildfires are also taking a personal toll on health care workers. CommuniCare’s Marshall lost her family’s home in rural Winters, along with 20 acres of olive trees and other plantings that surrounded it, in the Aug. 19 fires that swept through Solano County.

“They called it a ‘firenado,’ ” Marshall said. An apparent confluence of three fires raged out of control, demolishing thousands of acres. With her family safely accounted for and temporary housing arranged by a friend, she returned to work. “Our clinics interact with a very vulnerable population,” she said, “and this is a critical time for them.”

While she pondered how her family would rebuild, the CEO was faced with another immediate crisis: the clinic’s shortage of supplies. Last month, CommuniCare got down to 19 COVID test kits on hand, and ran so low on swabs “that we were literally turning to our veterinary friends for reinforcements,” the doctor said. The clinic’s COVID test results, meanwhile, were taking nearly two weeks to be returned from an overwhelmed outside lab, rendering contact tracing almost useless.

Those situations have been addressed, at least temporarily, Marshall said. But although the West Coast is in the most dangerous time of year for wildfires, generally September to December, another complication for health providers lies on the horizon: flu season.

The Southern Hemisphere, whose influenza trends during our summer months typically predict what’s to come for the U.S., has had very little of the disease this year, presumably because of restricted travel, social distancing and face masks. But it’s too early to be sure what the U.S. flu season will entail.

“You can start to see some cases of the flu in late October,” said Marshall, “and the reality is that it’s going to carry a number of characteristics that could also be symptomatic of COVID. And nothing changes: You have to rule it out, just to eliminate the risk.”

KHN (Kaiser Health News) is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente. This KHN story first published on California Healthline, a service of the California Health Care Foundation.

The patients walk into Dr. Melissa Marshall’s community clinics in Northern California with the telltale symptoms. They’re having trouble breathing. It may even hurt to inhale. They’ve got a cough, and the sore throat is definitely there.

A straight case of COVID-19? Not so fast. This is wildfire country.

Up and down the West Coast, hospitals and health facilities are reporting an influx of patients with problems most likely related to smoke inhalation. As fires rage largely uncontrolled amid dry heat and high winds, smoke and ash are billowing and settling on coastal areas like San Francisco and cities and towns hundreds of miles inland as well, turning the sky orange or gray and making even ordinary breathing difficult.

But that, Marshall said, is only part of the challenge. Facilities already strapped for testing supplies and personal protective equipment must first rule out COVID-19 in these patients, because many of the symptoms they present with are the same as those caused by the virus.

“Obviously, there’s overlap in the symptoms,” said Marshall, the CEO of CommuniCare, a collection of six clinics in Yolo County, near Sacramento, that treats mostly underinsured and uninsured patients. “Any time someone comes in with even some of those symptoms, we ask ourselves, ‘Is it COVID?’ At the end of the day, clinically speaking, I still want to rule out the virus.”

The protocol is to treat the symptoms, whatever their cause, while recommending that the patient quarantine until test results for the virus come back, she said.

It is a scene playing out in numerous hospitals. Administrators and physicians, finely attuned to COVID-19’s ability to spread quickly and wreak havoc, simply won’t take a chance when they recognize symptoms that could emanate from the virus.

“We’ve seen an increase in patients presenting to the emergency department with respiratory distress,” said Dr. Nanette Mickiewicz, president and CEO of Dominican Hospital in Santa Cruz. “As this can also be a symptom of COVID-19, we’re treating these patients as we would any person under investigation for coronavirus until we can rule them out through our screening process.” During the workup, symptoms that are more specific to COVID-19, like fever, would become apparent.

For the workers at Dominican, the issue moved to the top of the list quickly. Santa Cruz and San Mateo counties have borne the brunt of the CZU Lightning Complex fires, which as of Sept. 10 had burned more than 86,000 acres, destroying 1,100 structures and threatening more than 7,600 others. Nearly a month after they began, the fires were approximately 84% contained, but thousands of people remained evacuated.

Dominican, a Dignity Health hospital, is “open, safe and providing care,” Mickiewicz said. Multiple tents erected outside the building serve as an extension of its ER waiting room. They also are used to perform what has come to be understood as an essential role: separating those with symptoms of COVID-19 from those without.

At the two Solano County hospitals operated by NorthBay Healthcare, the path of some of the wildfires prompted officials to review their evacuation procedures, said spokesperson Steve Huddleston. They ultimately avoided the need to evacuate patients, and new ones arrived with COVID-like symptoms that may actually have been from smoke inhalation.

Huddleston said NorthBay’s intake process “calls for anyone with COVID characteristics to be handled as [a] patient under investigation for COVID, which means they’re separated, screened and managed by staff in special PPE.” At the two hospitals, which have handled nearly 200 COVID cases so far, the protocol is well established.

Hospitals in California, though not under siege in most cases, are dealing with multiple issues they might typically face only sporadically. In Napa County, Adventist Health St. Helena Hospital evacuated 51 patients on a single August night as a fire approached, moving them to 10 other facilities according to their needs and bed space. After a 10-day closure, the hospital was allowed to reopen as evacuation orders were lifted, the fire having been contained some distance away.

The wildfires are also taking a personal toll on health care workers. CommuniCare’s Marshall lost her family’s home in rural Winters, along with 20 acres of olive trees and other plantings that surrounded it, in the Aug. 19 fires that swept through Solano County.

“They called it a ‘firenado,’ ” Marshall said. An apparent confluence of three fires raged out of control, demolishing thousands of acres. With her family safely accounted for and temporary housing arranged by a friend, she returned to work. “Our clinics interact with a very vulnerable population,” she said, “and this is a critical time for them.”

While she pondered how her family would rebuild, the CEO was faced with another immediate crisis: the clinic’s shortage of supplies. Last month, CommuniCare got down to 19 COVID test kits on hand, and ran so low on swabs “that we were literally turning to our veterinary friends for reinforcements,” the doctor said. The clinic’s COVID test results, meanwhile, were taking nearly two weeks to be returned from an overwhelmed outside lab, rendering contact tracing almost useless.

Those situations have been addressed, at least temporarily, Marshall said. But although the West Coast is in the most dangerous time of year for wildfires, generally September to December, another complication for health providers lies on the horizon: flu season.

The Southern Hemisphere, whose influenza trends during our summer months typically predict what’s to come for the U.S., has had very little of the disease this year, presumably because of restricted travel, social distancing and face masks. But it’s too early to be sure what the U.S. flu season will entail.

“You can start to see some cases of the flu in late October,” said Marshall, “and the reality is that it’s going to carry a number of characteristics that could also be symptomatic of COVID. And nothing changes: You have to rule it out, just to eliminate the risk.”

KHN (Kaiser Health News) is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente. This KHN story first published on California Healthline, a service of the California Health Care Foundation.

Each year, the Society of Hospital Medicine celebrates the exemplary actions and successes of its members through the Awards of Excellence program. Nominations open every fall, providing the SHM community with the opportunity to nominate a peer, or themselves, to receive an esteemed award of excellence in an array of categories including Teaching, Outstanding Service in Hospital Medicine, Research, and so many others.

While the program and its Awards Committee review nominations with a predetermined set of criteria, excellence is not a ‘one-size-fits-all’ defined term.

Ms. Cowan is the marketing communications specialist at the Society of Hospital Medicine.

Each year, the Society of Hospital Medicine celebrates the exemplary actions and successes of its members through the Awards of Excellence program. Nominations open every fall, providing the SHM community with the opportunity to nominate a peer, or themselves, to receive an esteemed award of excellence in an array of categories including Teaching, Outstanding Service in Hospital Medicine, Research, and so many others.

While the program and its Awards Committee review nominations with a predetermined set of criteria, excellence is not a ‘one-size-fits-all’ defined term.

Ms. Cowan is the marketing communications specialist at the Society of Hospital Medicine.

Each year, the Society of Hospital Medicine celebrates the exemplary actions and successes of its members through the Awards of Excellence program. Nominations open every fall, providing the SHM community with the opportunity to nominate a peer, or themselves, to receive an esteemed award of excellence in an array of categories including Teaching, Outstanding Service in Hospital Medicine, Research, and so many others.

While the program and its Awards Committee review nominations with a predetermined set of criteria, excellence is not a ‘one-size-fits-all’ defined term.

Ms. Cowan is the marketing communications specialist at the Society of Hospital Medicine.

Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.

Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.

Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.

Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.

“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.

The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.

In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”

That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.

In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.

“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.

To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.

They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.

Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).

Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.

Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.

“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.

Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.

SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.

Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.

Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.

Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.

Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.

“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.

The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.

In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”

That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.

In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.

“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.

To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.

They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.

Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).

Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.

Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.

“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.

Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.

SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.

Continued use of tumor necrosis factor inhibitors or methotrexate is acceptable in most patients who acquire COVID-19, results of a recent cohort study suggest.

Among patients on tumor necrosis factor inhibitors (TNFi) or methotrexate who developed COVID-19, death and hospitalization rates were similar to matched COVID-19 patients not on those medications, according to authors of the multicenter research network study.

Reassuringly, likelihood of hospitalization and mortality were not significantly different between 214 patients with COVID-19 taking TNFi or methotrexate and 31,862 matched COVID-19 patients not on those medications, according to the investigators, whose findings were published recently in the Journal of the American Academy of Dermatology.

Zachary Zinn, MD, corresponding author on the study, said in an interview that the findings suggest these medicines can be safely continued in the majority of patients taking them during the COVID-19 pandemic.

“If you’re a prescribing physician who’s giving patients TNF inhibitors or methotrexate or both, I think you can comfortably tell your patients there is good data that these do not lead to worse outcomes if you get COVID-19,” said Dr. Zinn, associate professor in the department of dermatology at West Virginia University, Morgantown.

The findings from these researchers corroborate a growing body of evidence suggesting that immunosuppressive treatments can be continued in patients with dermatologic and rheumatic conditions.

In recent guidance from the National Psoriasis Foundation, released Sept. 4, an expert consensus panel cited 15 studies that they said suggested that treatments for psoriasis or psoriatic arthritis “do not meaningfully alter the risk of acquiring SARS-CoV-2 infection or having worse COVID-19 outcomes.”

That said, the data to date are mainly from small case series and registry studies based on spontaneously reported COVID-19 cases, which suggests a continued need for shared decision making. In addition, chronic systemic corticosteroids should be avoided for management of psoriatic arthritis, the guidance states, based on rheumatology and gastroenterology literature suggesting this treatment is linked to worse COVID-19 outcomes.

In the interview, Dr. Zinn noted that some previous studies of immunosuppressive treatments in patients who acquire COVID-19 have aggregated data on numerous classes of biologic medications, lessening the strength of data for each specific medication.

“By focusing specifically on TNF inhibitors and methotrexate, this study gives better guidance to prescribers of these medications,” he said.

To see whether TNFi or methotrexate increased risk of worsened COVID-19 outcomes, Dr. Zinn and coinvestigators evaluated data from TriNetX, a research network that includes approximately 53 million unique patient records, predominantly in the United States.

They identified 32,076 adult patients with COVID-19, of whom 214 had recent exposure to TNFi or methotrexate. The patients in the TNFi/methotrexate group were similar in age to those without exposure to those drugs, at 55.1 versus 53.2 years, respectively. However, patients in the drug exposure group were more frequently White, female, and had substantially more comorbidities, including diabetes and obesity, according to the investigators.

Nevertheless, the likelihood of hospitalization was not statistically different in the TNFi/methotrexate group versus the non-TNFi/methotrexate group, with a risk ratio of 0.91 (95% confidence interval, 0.68-1.22; P = .5260).

Likewise, the likelihood of death was not different between groups, with a RR of 0.87 (95% CI, 0.42-1.78; P = .6958). Looking at subgroups of patients exposed to TNFi or methotrexate only didn’t change the results, the investigators added.

Taken together, the findings argue against interruption of these treatments because of the fear of the possibly worse COVID-19 outcomes, the investigators concluded, although they emphasized the need for more research.

“Because the COVID-19 pandemic is ongoing, there is a desperate need for evidence-based data on biologic and immunomodulator exposure in the setting of COVID-19 infection,” they wrote.

Dr. Zinn and coauthors reported no conflicts of interest and no funding sources related to the study.

SOURCE: Zinn Z et al. J Am Acad Dermatol. 2020 Sep 11. doi: 10.1016/j.jaad.2020.09.009.

Obstructive sleep apnea (OSA) treatment with positive airway pressure (PAP) therapy was associated with a lower odds of incident Alzheimer’s disease and other dementia in a large retrospective cohort study of Medicare patients with the sleep disorder.

Courtesy ResMed

The study builds on research linking OSA to poor cognitive outcomes and dementia syndromes. With use of a 5% random sample of Medicare beneficiaries (more than 2.7 million) and their claims data, investigators identified approximately 53,000 who had an OSA diagnosis prior to 2011.

Of these Medicare beneficiaries, 78% with OSA were identified as “PAP-treated” based on having at least one durable medical equipment claim for PAP equipment. And of those treated, 74% were identified as “PAP adherent” based on having more than two PAP equipment claims separated by at least a month, said Galit Levi Dunietz, PhD, MPH, at the virtual annual meeting of the Associated Professional Sleep Societies.

Dr. Dunietz and her coinvestigators used logistic regression to examine the associations between PAP treatment and PAP treatment adherence, and incident ICD-9 diagnoses of Alzheimer’s disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) over the period 2011-2013.

After adjustments for potential confounders (age, sex, race, stroke, hypertension, cardiovascular disease, and depression), OSA treatment was associated with a significantly lower odds of a diagnosis of AD (odds ratio, 0.78; 95% confidence interval 0.69-0.89) or DNOS (OR, 0.69; 95% CI, 0.55-0.85), as well as nonsignificantly lower odds of MCI diagnosis (OR, 0.82; 95% CI, 0.66-1.02).

“People who are treated for OSA have a 22% reduced odds of being diagnosed with AD and a 31% reduced odds of getting DNOS,” said Dr. Dunietz, from the University of Michigan in Ann Arbor, in an interview after the meeting. “The 18% reduced odds of mild cognitive disorder is not really significant because the upper bound is 1.02, but we consider it approaching significance.”

Adherence to treatment was significantly associated with lower odds of AD, but not with significantly lower odds of DNOS or MCI, she said. OSA was confirmed by ICD-9 diagnosis codes plus the presence of relevant polysomnography current procedural terminology code.

All told, the findings “suggest that PAP therapy for OSA may lower short-term risk for dementia in older persons,” Dr. Dunietz and her co-nvestigators said in their poster presentation. “If a causal pathway exists between OSA and dementia, treatment of OSA may offer new opportunities to improve cognitive outcomes in older adults with OSA.”

Andrew W. Varga, MD, of the division of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Integrative Sleep Center, both in New York, said that cognitive impairment is now a recognized clinical consequence of OSA and that OSA treatment could be a target for the prevention of cognitive impairment and Alzheimer’s disease in particular.

“I absolutely bring it up with patients in their 60s and 70s. I’m honest – I say, there seems to be more and more evidence for links between apnea and Alzheimer’s in particular. I tell them we don’t know 100% whether PAP reverses any of this, but it stands to reason that it does,” said Dr. Varga, who was asked to comment on the study and related research.

An analysis published several years ago in Neurology from the Alzheimer’s Disease Neuroimaging Initiative cohort found that patients with self-reported sleep apnea had a younger age of MCI or AD onset (about 10 years) and that patients who used continuous positive airway pressure had a delayed age of onset. “Those who had a subjective diagnosis of sleep apnea and who also reported using CPAP as treatment seemed to go in the opposite direction,” said Dr. Varga, a coauthor of that study. “They had an onset of AD that looked just like people who had no sleep apnea.”

While this study was limited by sleep apnea being self-reported – and by the lack of severity data – the newly reported study may be limited by the use of ICD codes and the fact that OSA is often entered into patient’s chart before diagnosis is confirmed through a sleep study, Dr. Varga said.

“The field is mature enough that we should be thinking of doing honest and rigorous clinical trials for sleep apnea with cognitive outcomes being a main measure of interest,” he said. “The issue we’re struggling with in the field is that such a trial would not be short.”

There are several theories for the link between OSA and cognitive impairment, he said, including disruptions in sleep architecture leading to increased production of amyloid and tau and/or decreased “clearance” of extracellular amyloid, neuronal sensitivity to hypoxia, and cardiovascular comorbidities.

Dr. Dunietz’s study was supported by The American Academy of Sleep Medicine Foundation. She reported having no disclosures. Dr. Varga said he has no relevant disclosures.

Obstructive sleep apnea (OSA) treatment with positive airway pressure (PAP) therapy was associated with a lower odds of incident Alzheimer’s disease and other dementia in a large retrospective cohort study of Medicare patients with the sleep disorder.

Courtesy ResMed

The study builds on research linking OSA to poor cognitive outcomes and dementia syndromes. With use of a 5% random sample of Medicare beneficiaries (more than 2.7 million) and their claims data, investigators identified approximately 53,000 who had an OSA diagnosis prior to 2011.

Of these Medicare beneficiaries, 78% with OSA were identified as “PAP-treated” based on having at least one durable medical equipment claim for PAP equipment. And of those treated, 74% were identified as “PAP adherent” based on having more than two PAP equipment claims separated by at least a month, said Galit Levi Dunietz, PhD, MPH, at the virtual annual meeting of the Associated Professional Sleep Societies.

Dr. Dunietz and her coinvestigators used logistic regression to examine the associations between PAP treatment and PAP treatment adherence, and incident ICD-9 diagnoses of Alzheimer’s disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) over the period 2011-2013.

After adjustments for potential confounders (age, sex, race, stroke, hypertension, cardiovascular disease, and depression), OSA treatment was associated with a significantly lower odds of a diagnosis of AD (odds ratio, 0.78; 95% confidence interval 0.69-0.89) or DNOS (OR, 0.69; 95% CI, 0.55-0.85), as well as nonsignificantly lower odds of MCI diagnosis (OR, 0.82; 95% CI, 0.66-1.02).

“People who are treated for OSA have a 22% reduced odds of being diagnosed with AD and a 31% reduced odds of getting DNOS,” said Dr. Dunietz, from the University of Michigan in Ann Arbor, in an interview after the meeting. “The 18% reduced odds of mild cognitive disorder is not really significant because the upper bound is 1.02, but we consider it approaching significance.”

Adherence to treatment was significantly associated with lower odds of AD, but not with significantly lower odds of DNOS or MCI, she said. OSA was confirmed by ICD-9 diagnosis codes plus the presence of relevant polysomnography current procedural terminology code.

All told, the findings “suggest that PAP therapy for OSA may lower short-term risk for dementia in older persons,” Dr. Dunietz and her co-nvestigators said in their poster presentation. “If a causal pathway exists between OSA and dementia, treatment of OSA may offer new opportunities to improve cognitive outcomes in older adults with OSA.”

Andrew W. Varga, MD, of the division of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Integrative Sleep Center, both in New York, said that cognitive impairment is now a recognized clinical consequence of OSA and that OSA treatment could be a target for the prevention of cognitive impairment and Alzheimer’s disease in particular.

“I absolutely bring it up with patients in their 60s and 70s. I’m honest – I say, there seems to be more and more evidence for links between apnea and Alzheimer’s in particular. I tell them we don’t know 100% whether PAP reverses any of this, but it stands to reason that it does,” said Dr. Varga, who was asked to comment on the study and related research.

An analysis published several years ago in Neurology from the Alzheimer’s Disease Neuroimaging Initiative cohort found that patients with self-reported sleep apnea had a younger age of MCI or AD onset (about 10 years) and that patients who used continuous positive airway pressure had a delayed age of onset. “Those who had a subjective diagnosis of sleep apnea and who also reported using CPAP as treatment seemed to go in the opposite direction,” said Dr. Varga, a coauthor of that study. “They had an onset of AD that looked just like people who had no sleep apnea.”

While this study was limited by sleep apnea being self-reported – and by the lack of severity data – the newly reported study may be limited by the use of ICD codes and the fact that OSA is often entered into patient’s chart before diagnosis is confirmed through a sleep study, Dr. Varga said.

“The field is mature enough that we should be thinking of doing honest and rigorous clinical trials for sleep apnea with cognitive outcomes being a main measure of interest,” he said. “The issue we’re struggling with in the field is that such a trial would not be short.”

There are several theories for the link between OSA and cognitive impairment, he said, including disruptions in sleep architecture leading to increased production of amyloid and tau and/or decreased “clearance” of extracellular amyloid, neuronal sensitivity to hypoxia, and cardiovascular comorbidities.

Dr. Dunietz’s study was supported by The American Academy of Sleep Medicine Foundation. She reported having no disclosures. Dr. Varga said he has no relevant disclosures.

Obstructive sleep apnea (OSA) treatment with positive airway pressure (PAP) therapy was associated with a lower odds of incident Alzheimer’s disease and other dementia in a large retrospective cohort study of Medicare patients with the sleep disorder.

Courtesy ResMed

The study builds on research linking OSA to poor cognitive outcomes and dementia syndromes. With use of a 5% random sample of Medicare beneficiaries (more than 2.7 million) and their claims data, investigators identified approximately 53,000 who had an OSA diagnosis prior to 2011.

Of these Medicare beneficiaries, 78% with OSA were identified as “PAP-treated” based on having at least one durable medical equipment claim for PAP equipment. And of those treated, 74% were identified as “PAP adherent” based on having more than two PAP equipment claims separated by at least a month, said Galit Levi Dunietz, PhD, MPH, at the virtual annual meeting of the Associated Professional Sleep Societies.

Dr. Dunietz and her coinvestigators used logistic regression to examine the associations between PAP treatment and PAP treatment adherence, and incident ICD-9 diagnoses of Alzheimer’s disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) over the period 2011-2013.

After adjustments for potential confounders (age, sex, race, stroke, hypertension, cardiovascular disease, and depression), OSA treatment was associated with a significantly lower odds of a diagnosis of AD (odds ratio, 0.78; 95% confidence interval 0.69-0.89) or DNOS (OR, 0.69; 95% CI, 0.55-0.85), as well as nonsignificantly lower odds of MCI diagnosis (OR, 0.82; 95% CI, 0.66-1.02).

“People who are treated for OSA have a 22% reduced odds of being diagnosed with AD and a 31% reduced odds of getting DNOS,” said Dr. Dunietz, from the University of Michigan in Ann Arbor, in an interview after the meeting. “The 18% reduced odds of mild cognitive disorder is not really significant because the upper bound is 1.02, but we consider it approaching significance.”

Adherence to treatment was significantly associated with lower odds of AD, but not with significantly lower odds of DNOS or MCI, she said. OSA was confirmed by ICD-9 diagnosis codes plus the presence of relevant polysomnography current procedural terminology code.

All told, the findings “suggest that PAP therapy for OSA may lower short-term risk for dementia in older persons,” Dr. Dunietz and her co-nvestigators said in their poster presentation. “If a causal pathway exists between OSA and dementia, treatment of OSA may offer new opportunities to improve cognitive outcomes in older adults with OSA.”

Andrew W. Varga, MD, of the division of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Integrative Sleep Center, both in New York, said that cognitive impairment is now a recognized clinical consequence of OSA and that OSA treatment could be a target for the prevention of cognitive impairment and Alzheimer’s disease in particular.

“I absolutely bring it up with patients in their 60s and 70s. I’m honest – I say, there seems to be more and more evidence for links between apnea and Alzheimer’s in particular. I tell them we don’t know 100% whether PAP reverses any of this, but it stands to reason that it does,” said Dr. Varga, who was asked to comment on the study and related research.

An analysis published several years ago in Neurology from the Alzheimer’s Disease Neuroimaging Initiative cohort found that patients with self-reported sleep apnea had a younger age of MCI or AD onset (about 10 years) and that patients who used continuous positive airway pressure had a delayed age of onset. “Those who had a subjective diagnosis of sleep apnea and who also reported using CPAP as treatment seemed to go in the opposite direction,” said Dr. Varga, a coauthor of that study. “They had an onset of AD that looked just like people who had no sleep apnea.”

While this study was limited by sleep apnea being self-reported – and by the lack of severity data – the newly reported study may be limited by the use of ICD codes and the fact that OSA is often entered into patient’s chart before diagnosis is confirmed through a sleep study, Dr. Varga said.

“The field is mature enough that we should be thinking of doing honest and rigorous clinical trials for sleep apnea with cognitive outcomes being a main measure of interest,” he said. “The issue we’re struggling with in the field is that such a trial would not be short.”

There are several theories for the link between OSA and cognitive impairment, he said, including disruptions in sleep architecture leading to increased production of amyloid and tau and/or decreased “clearance” of extracellular amyloid, neuronal sensitivity to hypoxia, and cardiovascular comorbidities.

Dr. Dunietz’s study was supported by The American Academy of Sleep Medicine Foundation. She reported having no disclosures. Dr. Varga said he has no relevant disclosures.

Consuming more milk, cheese, or yogurt might be a simple, low-cost way to boost bone health and prevent some falls and fractures in older people living in long-term care facilities, according to a new randomized study from Australia.

“Supplementation using dairy foods is likely to be an effective, safe, widely available, and low cost means of curtailing the public health burden of fractures,” said Sandra Iuliano, PhD, from the University of Melbourne, who presented the findings during the virtual American Society of Bone and Mineral Research 2020 annual meeting.

The researchers randomized 60 old-age institutions to provide residents with their usual menus or a diet with more milk, cheese, or yogurt for 2 years.

The residents with the altered menus increased their dairy consumption from 2 servings/day to 3.5 servings/day, which was reflected in a greater intake of calcium and protein, along with fewer falls, total fractures, and hip fractures than in the control group.

“This is the first randomized trial to show a benefit of dairy food intake on risk of fractures,” Walter Willett, MD, DrPH, professor of nutrition and epidemiology at the Harvard School of Public Health, Boston, said in an interview.

The results are “not surprising” because supplements of calcium plus vitamin D have reduced the risk of fractures in a similar population of older residents living in special living facilities, said Dr. Willett, coauthor of a recent review article, “Milk and Health,” published in the New England Journal of Medicine.

“It is important for everyone to have adequate intake of calcium and vitamin D,” he said. However, “it isn’t clear whether it is better to ensure this clinically by supplements, overall healthy diet, or extra dairy intake,” he added, noting that consuming the amount of dairy given in this Australian study is not environmentally sustainable.

Clifford Rosen, MD, professor of medicine, Tufts University, Boston, said in an interview that the Australian researchers studied the impact of increased dietary calcium and protein, not the impact of vitamin D via supplements.

“This is progress toward getting interventions to our most needy residents to prevent fractures – probably the most compelling data that we have had in a number of years,” he noted.

The current study shows “it’s not [the] vitamin D,” because the residents had initial low calcium levels but normal vitamin D levels. “For too long we’ve been stuck on the idea that it is [increasing] vitamin D in the elderly that causes a reduction in fractures,” said Dr. Rosen. “The data are not very supportive of it, but people continue to think that’s the most important element.”

On the other hand, the current study raises certain questions. “What we don’t know is, is it the calcium, or is it the protein, or the combination, that had an impact?”

Would upping dairy decrease falls?

Older adults living in institutions have a high risk of falls and fractures, including hip fractures, and “malnutrition is common,” said Dr. Iuliano during her presentation.

Prior studies have reported that such residents have a daily dietary calcium intake of 635 mg (half the recommended 1,300 mg), a protein intake of 0.8 g/kg body weight (less than the recommended 1 g/kg body weight), and a dairy intake of 1.5 servings (about a third of the recommended amount), she said.

The group hypothesized that upping dairy intake of elderly residents living in long-term care institutions would reduce the risk of fractures. They performed a 2-year cluster-randomized trial in 60 facilities in Melbourne and surrounding areas.

Half gave their 3,301 residents menus with a higher dairy content, and the other half gave their 3,894 residents (controls) the usual menus.

The residents in both groups had similar characteristics: they were a mean age of 87 years and 68% were women. A subgroup had blood tests and bone morphology studies at baseline and 1 year.

Researchers verified nutrient intake by analyzing the menus and doing plate waste analysis for a subgroup, and they determined the number of falls and fractures from incident and hospital x-ray reports, respectively.
 

One-third fewer fractures in the higher-dairy group

At the study start, residents in both groups had similar vitamin D levels (72 nmol/L) and bone morphology. They were consuming two servings of dairy food and drink a day, where a serving was 250 mL of milk (including lactose-free milk) or 200 g of yogurt or 40 g of cheese.

Their initial daily calcium intake was 650 mg, which stayed the same in the control group, but increased to >1100 mg in the intervention group.

Their initial daily protein intake was around 59 g, which remained the same in the control group, but increased to about 72 grams (1.1 g/kg body weight) in the intervention group.

At 2 years, the 1.5 servings/day increase in dairy intake in the control versus intervention group was associated with an 11% reduction in falls (62% vs. 57%), a 33% reduction in fractures (5.2% vs. 3.7%), a 46% reduction in hip fractures (2.4% vs. 1.3%), and no difference in mortality (28% in both groups).

The intervention was also associated with a slowing in bone loss and an increase in insulinlike growth factor–1.
 

Four dairy servings a day “is high”

Dr. Willett said that “it is reasonable for seniors to take one or two servings of dairy per day, but four servings per day, as in this study, is probably not necessary.”

Moreover, “dairy production has a major impact on greenhouse gas emissions, and even two servings per day would not be environmentally sustainable if everyone were to consume this amount,” he observed.

“Because the world is facing an existential threat from climate change, general advice to consume high amounts of dairy products would be irresponsible as we can get all essential nutrients from other sources,” he added. “That said, modest amounts of dairy foods, such as one to two servings per day could be reasonable. There is some suggestive evidence that dairy in the form of yogurt may have particular benefits.”

The study was funded by Melbourne University and various dietary councils. Dr. Iuliano reported receiving lecture fees from Abbott. Dr. Rosen and Dr. Willett reported no relevant financial relationships.

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

Consuming more milk, cheese, or yogurt might be a simple, low-cost way to boost bone health and prevent some falls and fractures in older people living in long-term care facilities, according to a new randomized study from Australia.

“Supplementation using dairy foods is likely to be an effective, safe, widely available, and low cost means of curtailing the public health burden of fractures,” said Sandra Iuliano, PhD, from the University of Melbourne, who presented the findings during the virtual American Society of Bone and Mineral Research 2020 annual meeting.

The researchers randomized 60 old-age institutions to provide residents with their usual menus or a diet with more milk, cheese, or yogurt for 2 years.

The residents with the altered menus increased their dairy consumption from 2 servings/day to 3.5 servings/day, which was reflected in a greater intake of calcium and protein, along with fewer falls, total fractures, and hip fractures than in the control group.

“This is the first randomized trial to show a benefit of dairy food intake on risk of fractures,” Walter Willett, MD, DrPH, professor of nutrition and epidemiology at the Harvard School of Public Health, Boston, said in an interview.

The results are “not surprising” because supplements of calcium plus vitamin D have reduced the risk of fractures in a similar population of older residents living in special living facilities, said Dr. Willett, coauthor of a recent review article, “Milk and Health,” published in the New England Journal of Medicine.

“It is important for everyone to have adequate intake of calcium and vitamin D,” he said. However, “it isn’t clear whether it is better to ensure this clinically by supplements, overall healthy diet, or extra dairy intake,” he added, noting that consuming the amount of dairy given in this Australian study is not environmentally sustainable.

Clifford Rosen, MD, professor of medicine, Tufts University, Boston, said in an interview that the Australian researchers studied the impact of increased dietary calcium and protein, not the impact of vitamin D via supplements.

“This is progress toward getting interventions to our most needy residents to prevent fractures – probably the most compelling data that we have had in a number of years,” he noted.

The current study shows “it’s not [the] vitamin D,” because the residents had initial low calcium levels but normal vitamin D levels. “For too long we’ve been stuck on the idea that it is [increasing] vitamin D in the elderly that causes a reduction in fractures,” said Dr. Rosen. “The data are not very supportive of it, but people continue to think that’s the most important element.”

On the other hand, the current study raises certain questions. “What we don’t know is, is it the calcium, or is it the protein, or the combination, that had an impact?”

Would upping dairy decrease falls?

Older adults living in institutions have a high risk of falls and fractures, including hip fractures, and “malnutrition is common,” said Dr. Iuliano during her presentation.

Prior studies have reported that such residents have a daily dietary calcium intake of 635 mg (half the recommended 1,300 mg), a protein intake of 0.8 g/kg body weight (less than the recommended 1 g/kg body weight), and a dairy intake of 1.5 servings (about a third of the recommended amount), she said.

The group hypothesized that upping dairy intake of elderly residents living in long-term care institutions would reduce the risk of fractures. They performed a 2-year cluster-randomized trial in 60 facilities in Melbourne and surrounding areas.

Half gave their 3,301 residents menus with a higher dairy content, and the other half gave their 3,894 residents (controls) the usual menus.

The residents in both groups had similar characteristics: they were a mean age of 87 years and 68% were women. A subgroup had blood tests and bone morphology studies at baseline and 1 year.

Researchers verified nutrient intake by analyzing the menus and doing plate waste analysis for a subgroup, and they determined the number of falls and fractures from incident and hospital x-ray reports, respectively.
 

One-third fewer fractures in the higher-dairy group

At the study start, residents in both groups had similar vitamin D levels (72 nmol/L) and bone morphology. They were consuming two servings of dairy food and drink a day, where a serving was 250 mL of milk (including lactose-free milk) or 200 g of yogurt or 40 g of cheese.

Their initial daily calcium intake was 650 mg, which stayed the same in the control group, but increased to >1100 mg in the intervention group.

Their initial daily protein intake was around 59 g, which remained the same in the control group, but increased to about 72 grams (1.1 g/kg body weight) in the intervention group.

At 2 years, the 1.5 servings/day increase in dairy intake in the control versus intervention group was associated with an 11% reduction in falls (62% vs. 57%), a 33% reduction in fractures (5.2% vs. 3.7%), a 46% reduction in hip fractures (2.4% vs. 1.3%), and no difference in mortality (28% in both groups).

The intervention was also associated with a slowing in bone loss and an increase in insulinlike growth factor–1.
 

Four dairy servings a day “is high”

Dr. Willett said that “it is reasonable for seniors to take one or two servings of dairy per day, but four servings per day, as in this study, is probably not necessary.”

Moreover, “dairy production has a major impact on greenhouse gas emissions, and even two servings per day would not be environmentally sustainable if everyone were to consume this amount,” he observed.

“Because the world is facing an existential threat from climate change, general advice to consume high amounts of dairy products would be irresponsible as we can get all essential nutrients from other sources,” he added. “That said, modest amounts of dairy foods, such as one to two servings per day could be reasonable. There is some suggestive evidence that dairy in the form of yogurt may have particular benefits.”

The study was funded by Melbourne University and various dietary councils. Dr. Iuliano reported receiving lecture fees from Abbott. Dr. Rosen and Dr. Willett reported no relevant financial relationships.

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

Consuming more milk, cheese, or yogurt might be a simple, low-cost way to boost bone health and prevent some falls and fractures in older people living in long-term care facilities, according to a new randomized study from Australia.

“Supplementation using dairy foods is likely to be an effective, safe, widely available, and low cost means of curtailing the public health burden of fractures,” said Sandra Iuliano, PhD, from the University of Melbourne, who presented the findings during the virtual American Society of Bone and Mineral Research 2020 annual meeting.

The researchers randomized 60 old-age institutions to provide residents with their usual menus or a diet with more milk, cheese, or yogurt for 2 years.

The residents with the altered menus increased their dairy consumption from 2 servings/day to 3.5 servings/day, which was reflected in a greater intake of calcium and protein, along with fewer falls, total fractures, and hip fractures than in the control group.

“This is the first randomized trial to show a benefit of dairy food intake on risk of fractures,” Walter Willett, MD, DrPH, professor of nutrition and epidemiology at the Harvard School of Public Health, Boston, said in an interview.

The results are “not surprising” because supplements of calcium plus vitamin D have reduced the risk of fractures in a similar population of older residents living in special living facilities, said Dr. Willett, coauthor of a recent review article, “Milk and Health,” published in the New England Journal of Medicine.

“It is important for everyone to have adequate intake of calcium and vitamin D,” he said. However, “it isn’t clear whether it is better to ensure this clinically by supplements, overall healthy diet, or extra dairy intake,” he added, noting that consuming the amount of dairy given in this Australian study is not environmentally sustainable.

Clifford Rosen, MD, professor of medicine, Tufts University, Boston, said in an interview that the Australian researchers studied the impact of increased dietary calcium and protein, not the impact of vitamin D via supplements.

“This is progress toward getting interventions to our most needy residents to prevent fractures – probably the most compelling data that we have had in a number of years,” he noted.

The current study shows “it’s not [the] vitamin D,” because the residents had initial low calcium levels but normal vitamin D levels. “For too long we’ve been stuck on the idea that it is [increasing] vitamin D in the elderly that causes a reduction in fractures,” said Dr. Rosen. “The data are not very supportive of it, but people continue to think that’s the most important element.”

On the other hand, the current study raises certain questions. “What we don’t know is, is it the calcium, or is it the protein, or the combination, that had an impact?”

Would upping dairy decrease falls?

Older adults living in institutions have a high risk of falls and fractures, including hip fractures, and “malnutrition is common,” said Dr. Iuliano during her presentation.

Prior studies have reported that such residents have a daily dietary calcium intake of 635 mg (half the recommended 1,300 mg), a protein intake of 0.8 g/kg body weight (less than the recommended 1 g/kg body weight), and a dairy intake of 1.5 servings (about a third of the recommended amount), she said.

The group hypothesized that upping dairy intake of elderly residents living in long-term care institutions would reduce the risk of fractures. They performed a 2-year cluster-randomized trial in 60 facilities in Melbourne and surrounding areas.

Half gave their 3,301 residents menus with a higher dairy content, and the other half gave their 3,894 residents (controls) the usual menus.

The residents in both groups had similar characteristics: they were a mean age of 87 years and 68% were women. A subgroup had blood tests and bone morphology studies at baseline and 1 year.

Researchers verified nutrient intake by analyzing the menus and doing plate waste analysis for a subgroup, and they determined the number of falls and fractures from incident and hospital x-ray reports, respectively.
 

One-third fewer fractures in the higher-dairy group

At the study start, residents in both groups had similar vitamin D levels (72 nmol/L) and bone morphology. They were consuming two servings of dairy food and drink a day, where a serving was 250 mL of milk (including lactose-free milk) or 200 g of yogurt or 40 g of cheese.

Their initial daily calcium intake was 650 mg, which stayed the same in the control group, but increased to >1100 mg in the intervention group.

Their initial daily protein intake was around 59 g, which remained the same in the control group, but increased to about 72 grams (1.1 g/kg body weight) in the intervention group.

At 2 years, the 1.5 servings/day increase in dairy intake in the control versus intervention group was associated with an 11% reduction in falls (62% vs. 57%), a 33% reduction in fractures (5.2% vs. 3.7%), a 46% reduction in hip fractures (2.4% vs. 1.3%), and no difference in mortality (28% in both groups).

The intervention was also associated with a slowing in bone loss and an increase in insulinlike growth factor–1.
 

Four dairy servings a day “is high”

Dr. Willett said that “it is reasonable for seniors to take one or two servings of dairy per day, but four servings per day, as in this study, is probably not necessary.”

Moreover, “dairy production has a major impact on greenhouse gas emissions, and even two servings per day would not be environmentally sustainable if everyone were to consume this amount,” he observed.

“Because the world is facing an existential threat from climate change, general advice to consume high amounts of dairy products would be irresponsible as we can get all essential nutrients from other sources,” he added. “That said, modest amounts of dairy foods, such as one to two servings per day could be reasonable. There is some suggestive evidence that dairy in the form of yogurt may have particular benefits.”

The study was funded by Melbourne University and various dietary councils. Dr. Iuliano reported receiving lecture fees from Abbott. Dr. Rosen and Dr. Willett reported no relevant financial relationships.

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

The US Department of Veterans Affairs (VA) is embracing clinical trials with a focus on oncology, and patients will benefit from new priorities and programs, VA officials reported at the Association of VA Hematology/Oncology (AVAHO) virtual meeting. “The whole model is one that is far more proactive,” said Carolyn Clancy, MD, Under Secretary for Health for Discovery, Education, and Affiliate Networks.

According to Clancy, the department’s top research priority is to increase veteran access to high-quality clinical trials. “Priority number 2 is increasing the real-world impact of VA research,” she said. “Our commitment to veterans and the taxpayers is to reverse and shorten the [research-to-implementation] timeline. And the third priority is to put VA data to work for veterans, not just through people who work in VA and Veterans Health Administration, but through other researchers who can have access to them.”

To meet these goals, VA is engaging in multiple research programs and collaborations. Rachel B. Ramoni, DMD, ScD, the VA chief research and development officer, highlighted a number of the projects in a separate AVAHO meeting presentation, including:

• The National Cancer Institute and VA Interagency Group to Accelerate Trials Enrollment (NAVIGATE), an interagency collaboration between the VA and the National Cancer Institute (NCI). This program established a network of sites to help enrolled veterans take part in NCI-supported clinical trials. “It really got up and running in 2018, and I’m proud to say that over 250 veterans have been enrolled, and enrollment exceeds that at non-NAVIGATE sites,” Ramoni reported. “Clearly, the additional support that these sites are getting is really helping to achieve the outcome of getting more veterans access to these trials.” However, she said, some areas of the nation aren’t yet covered by the program.
• The Precision Oncology Program for Cancer of the Prostate (POPCaP), established through a partnership with the Prostate Cancer Foundation. The foundation provided a $50 million investment. “This program ensures that veterans, no matter where they are, get best-in-class prostate cancer care,” Ramoni explained. “The initial focus was ensuring that men get sequencing if they have metastatic prostate cancer, and that they get access to clinical trials. The really distinguishing factor about POPCaP is that it has built a vibrant community of clinicians, researchers and program offices. The whole is much greater than the sum of its parts.” More POPCaP hubs are in development, she said.
• PATCH (Prostate Cancer Analysis for Therapy Choice), a program funded by the VA and the Prostate Cancer Foundation. “The whole purpose of PATCH is to create this network of sites to systematically go through different clinical trials that are biomarker-driven,” Ramoni said. “One of the great things about PATCH is that it’s leveraging the genetics databases to help proactively identify men who might qualify for these trials and to find them wherever they might be across the system so they have access to these trials.” She also praised the program’s commitment to collaboration and mentorship. “If you’re new to putting together clinical trials concepts or to submitting merit proposals to VA for funding, PATCH is a great place to get into a community that’s supportive and wants to help you succeed.”
• The VA Phenomics Library. This library, based at the Boston VA Medical Center, focuses on improving the analysis of “messy” electronic health record data, Ramoni noted. “There are automated algorithms that go through and help you clean up that data to make sense of it,” she said. “The problem is that it’s really been an every-person-for-himself-or-herself system. Each researcher who needed these phenotypes was creating his or her own.” The Phenomics Library will promote sharing “so there’s not going to be as much wasted time duplicating effort,” she said. “By the end of fiscal year 2021, we will have over 1,000 curated phenotypes in there. We hope that will be a great resource for the oncology community as well as many other communities.”
• Access to Clinical Trials (ACT) for Veterans. “This program, which began a couple of years ago, has really succeeded,” Ramoni said. “We were focusing on decreasing the time it takes to start up multi-site industry trials. When we got started with ACT, it was taking over 200 days to get started. And now, just a couple years later, we are well under 100 days, which is within industry standards.” Also, she said, the VA established a Partnered Research Program office, “which serves to interact with our industry partners and really guide them through the VA system, which can be complex if you’re approaching it for the first time.”

In a separate presentation, Krissa Caroff, MS, CPC, program manager of the Partnered Research Program, said it had quickened the process of implementing clinical trials by tackling roadblocks such as the need for multiple master agreements to be signed. Central coordination has been key, she said, “and we are working closely to ensure that we when have a multisite trial, all the VA sites are utilizing the same single IRB [institutional review board]. We’ve also identified the critical information that we need to collect from industry in order for us to evaluate a trial.”

What’s next? “We really are going to be focusing on oncology trials,” Ramoni insisted. “This is a high priority for us.” She added: “Please share your feedback and experiences with us. And also please communicate amongst your colleagues within your organization to explain how we’re standardizing things within VA.”

The speakers reported no relevant disclosures.  

The US Department of Veterans Affairs (VA) is embracing clinical trials with a focus on oncology, and patients will benefit from new priorities and programs, VA officials reported at the Association of VA Hematology/Oncology (AVAHO) virtual meeting. “The whole model is one that is far more proactive,” said Carolyn Clancy, MD, Under Secretary for Health for Discovery, Education, and Affiliate Networks.

According to Clancy, the department’s top research priority is to increase veteran access to high-quality clinical trials. “Priority number 2 is increasing the real-world impact of VA research,” she said. “Our commitment to veterans and the taxpayers is to reverse and shorten the [research-to-implementation] timeline. And the third priority is to put VA data to work for veterans, not just through people who work in VA and Veterans Health Administration, but through other researchers who can have access to them.”

To meet these goals, VA is engaging in multiple research programs and collaborations. Rachel B. Ramoni, DMD, ScD, the VA chief research and development officer, highlighted a number of the projects in a separate AVAHO meeting presentation, including:

• The National Cancer Institute and VA Interagency Group to Accelerate Trials Enrollment (NAVIGATE), an interagency collaboration between the VA and the National Cancer Institute (NCI). This program established a network of sites to help enrolled veterans take part in NCI-supported clinical trials. “It really got up and running in 2018, and I’m proud to say that over 250 veterans have been enrolled, and enrollment exceeds that at non-NAVIGATE sites,” Ramoni reported. “Clearly, the additional support that these sites are getting is really helping to achieve the outcome of getting more veterans access to these trials.” However, she said, some areas of the nation aren’t yet covered by the program.
• The Precision Oncology Program for Cancer of the Prostate (POPCaP), established through a partnership with the Prostate Cancer Foundation. The foundation provided a $50 million investment. “This program ensures that veterans, no matter where they are, get best-in-class prostate cancer care,” Ramoni explained. “The initial focus was ensuring that men get sequencing if they have metastatic prostate cancer, and that they get access to clinical trials. The really distinguishing factor about POPCaP is that it has built a vibrant community of clinicians, researchers and program offices. The whole is much greater than the sum of its parts.” More POPCaP hubs are in development, she said.
• PATCH (Prostate Cancer Analysis for Therapy Choice), a program funded by the VA and the Prostate Cancer Foundation. “The whole purpose of PATCH is to create this network of sites to systematically go through different clinical trials that are biomarker-driven,” Ramoni said. “One of the great things about PATCH is that it’s leveraging the genetics databases to help proactively identify men who might qualify for these trials and to find them wherever they might be across the system so they have access to these trials.” She also praised the program’s commitment to collaboration and mentorship. “If you’re new to putting together clinical trials concepts or to submitting merit proposals to VA for funding, PATCH is a great place to get into a community that’s supportive and wants to help you succeed.”
• The VA Phenomics Library. This library, based at the Boston VA Medical Center, focuses on improving the analysis of “messy” electronic health record data, Ramoni noted. “There are automated algorithms that go through and help you clean up that data to make sense of it,” she said. “The problem is that it’s really been an every-person-for-himself-or-herself system. Each researcher who needed these phenotypes was creating his or her own.” The Phenomics Library will promote sharing “so there’s not going to be as much wasted time duplicating effort,” she said. “By the end of fiscal year 2021, we will have over 1,000 curated phenotypes in there. We hope that will be a great resource for the oncology community as well as many other communities.”
• Access to Clinical Trials (ACT) for Veterans. “This program, which began a couple of years ago, has really succeeded,” Ramoni said. “We were focusing on decreasing the time it takes to start up multi-site industry trials. When we got started with ACT, it was taking over 200 days to get started. And now, just a couple years later, we are well under 100 days, which is within industry standards.” Also, she said, the VA established a Partnered Research Program office, “which serves to interact with our industry partners and really guide them through the VA system, which can be complex if you’re approaching it for the first time.”

In a separate presentation, Krissa Caroff, MS, CPC, program manager of the Partnered Research Program, said it had quickened the process of implementing clinical trials by tackling roadblocks such as the need for multiple master agreements to be signed. Central coordination has been key, she said, “and we are working closely to ensure that we when have a multisite trial, all the VA sites are utilizing the same single IRB [institutional review board]. We’ve also identified the critical information that we need to collect from industry in order for us to evaluate a trial.”

What’s next? “We really are going to be focusing on oncology trials,” Ramoni insisted. “This is a high priority for us.” She added: “Please share your feedback and experiences with us. And also please communicate amongst your colleagues within your organization to explain how we’re standardizing things within VA.”

The speakers reported no relevant disclosures.  

The US Department of Veterans Affairs (VA) is embracing clinical trials with a focus on oncology, and patients will benefit from new priorities and programs, VA officials reported at the Association of VA Hematology/Oncology (AVAHO) virtual meeting. “The whole model is one that is far more proactive,” said Carolyn Clancy, MD, Under Secretary for Health for Discovery, Education, and Affiliate Networks.

According to Clancy, the department’s top research priority is to increase veteran access to high-quality clinical trials. “Priority number 2 is increasing the real-world impact of VA research,” she said. “Our commitment to veterans and the taxpayers is to reverse and shorten the [research-to-implementation] timeline. And the third priority is to put VA data to work for veterans, not just through people who work in VA and Veterans Health Administration, but through other researchers who can have access to them.”

To meet these goals, VA is engaging in multiple research programs and collaborations. Rachel B. Ramoni, DMD, ScD, the VA chief research and development officer, highlighted a number of the projects in a separate AVAHO meeting presentation, including:

• The National Cancer Institute and VA Interagency Group to Accelerate Trials Enrollment (NAVIGATE), an interagency collaboration between the VA and the National Cancer Institute (NCI). This program established a network of sites to help enrolled veterans take part in NCI-supported clinical trials. “It really got up and running in 2018, and I’m proud to say that over 250 veterans have been enrolled, and enrollment exceeds that at non-NAVIGATE sites,” Ramoni reported. “Clearly, the additional support that these sites are getting is really helping to achieve the outcome of getting more veterans access to these trials.” However, she said, some areas of the nation aren’t yet covered by the program.
• The Precision Oncology Program for Cancer of the Prostate (POPCaP), established through a partnership with the Prostate Cancer Foundation. The foundation provided a $50 million investment. “This program ensures that veterans, no matter where they are, get best-in-class prostate cancer care,” Ramoni explained. “The initial focus was ensuring that men get sequencing if they have metastatic prostate cancer, and that they get access to clinical trials. The really distinguishing factor about POPCaP is that it has built a vibrant community of clinicians, researchers and program offices. The whole is much greater than the sum of its parts.” More POPCaP hubs are in development, she said.
• PATCH (Prostate Cancer Analysis for Therapy Choice), a program funded by the VA and the Prostate Cancer Foundation. “The whole purpose of PATCH is to create this network of sites to systematically go through different clinical trials that are biomarker-driven,” Ramoni said. “One of the great things about PATCH is that it’s leveraging the genetics databases to help proactively identify men who might qualify for these trials and to find them wherever they might be across the system so they have access to these trials.” She also praised the program’s commitment to collaboration and mentorship. “If you’re new to putting together clinical trials concepts or to submitting merit proposals to VA for funding, PATCH is a great place to get into a community that’s supportive and wants to help you succeed.”
• The VA Phenomics Library. This library, based at the Boston VA Medical Center, focuses on improving the analysis of “messy” electronic health record data, Ramoni noted. “There are automated algorithms that go through and help you clean up that data to make sense of it,” she said. “The problem is that it’s really been an every-person-for-himself-or-herself system. Each researcher who needed these phenotypes was creating his or her own.” The Phenomics Library will promote sharing “so there’s not going to be as much wasted time duplicating effort,” she said. “By the end of fiscal year 2021, we will have over 1,000 curated phenotypes in there. We hope that will be a great resource for the oncology community as well as many other communities.”
• Access to Clinical Trials (ACT) for Veterans. “This program, which began a couple of years ago, has really succeeded,” Ramoni said. “We were focusing on decreasing the time it takes to start up multi-site industry trials. When we got started with ACT, it was taking over 200 days to get started. And now, just a couple years later, we are well under 100 days, which is within industry standards.” Also, she said, the VA established a Partnered Research Program office, “which serves to interact with our industry partners and really guide them through the VA system, which can be complex if you’re approaching it for the first time.”

In a separate presentation, Krissa Caroff, MS, CPC, program manager of the Partnered Research Program, said it had quickened the process of implementing clinical trials by tackling roadblocks such as the need for multiple master agreements to be signed. Central coordination has been key, she said, “and we are working closely to ensure that we when have a multisite trial, all the VA sites are utilizing the same single IRB [institutional review board]. We’ve also identified the critical information that we need to collect from industry in order for us to evaluate a trial.”

What’s next? “We really are going to be focusing on oncology trials,” Ramoni insisted. “This is a high priority for us.” She added: “Please share your feedback and experiences with us. And also please communicate amongst your colleagues within your organization to explain how we’re standardizing things within VA.”

The speakers reported no relevant disclosures.  

Patient outcomes after gender-affirming vaginoplasty may improve as surgeons gain experience with the procedure, research suggests. For one surgeon, certain adverse events, including the need for revision surgery, were less likely after 50 cases.

“As surgical programs evolve, the important question becomes: At what case threshold are cases performed safely, efficiently, and with favorable outcomes?” said Cecile A. Ferrando, MD, MPH, program director of the female pelvic medicine and reconstructive surgery fellowship at Cleveland Clinic and director of the transgender surgery and medicine program in the Cleveland Clinic’s Center for LGBT Care.

The answer could guide training for future surgeons, Dr. Ferrando said at the virtual annual scientific meeting of the Society of Gynecologic Surgeons. Future studies should include patient-centered outcomes and data from multiple centers, other doctors said.

Transgender women who opt to surgically transition may undergo vaginoplasty. Although many reports describe surgical techniques, “there is a paucity of evidence-based data as well as few reports on outcomes,” Dr. Ferrando noted.

To describe perioperative adverse events related to vaginoplasty performed for gender affirmation and determine a minimum number of cases needed to reduce their likelihood, Dr. Ferrando performed a retrospective study of 76 patients. The patients underwent surgery between December 2015 and March 2019 and had 6-month postoperative outcomes available. Dr. Ferrando performed the procedures.

Dr. Ferrando evaluated outcomes after increments of 10 cases. After 50 cases, the median surgical time decreased to approximately 180 minutes, which an informal survey of surgeons suggested was efficient, and the rates of adverse events were similar to those in other studies. Dr. Ferrando compared outcomes from the first 50 cases with outcomes from the 26 cases that followed.

Overall, the patients had a mean age of 41 years. The first 50 patients were older on average (44 years vs. 35 years). About 83% underwent full-depth vaginoplasty. The incidence of intraoperative and immediate postoperative events was low and did not differ between the two groups. Rates of delayed postoperative events – those occurring 30 or more days after surgery – did significantly differ between the two groups, however.

After 50 cases, there was a lower incidence of urinary stream abnormalities (7.7% vs. 16.3%), introital stenosis (3.9% vs. 12%), and revision surgery (that is, elective, cosmetic, or functional revision within 6 months; 19.2% vs. 44%), compared with the first 50 cases.

The study did not include patient-centered outcomes and the results may have limited generalizability, Dr. Ferrando noted. “The incidence of serious adverse events related to vaginoplasty is low while minor events are common,” she said. “A 50-case minimum may be an adequate case number target for postgraduate trainees learning how to do this surgery.”

“I learned that the incidence of serious complications, like injuries during the surgery, or serious events immediately after surgery was quite low, which was reassuring,” Dr. Ferrando said in a later interview. “The cosmetic result and detail that is involved with the surgery – something that is very important to patients – that skill set takes time and experience to refine.”

Subsequent studies should include patient-centered outcomes, which may help surgeons understand potential “sources of consternation for patients,” such as persistent corporal tissue, poor aesthetics, vaginal stenosis, urinary meatus location, and clitoral hooding, Joseph J. Pariser, MD, commented in an interview. Dr. Pariser, a urologist who specializes in gender care at the University of Minnesota in Minneapolis, in 2019 reviewed safety outcomes from published case series.

“In my own practice, precise placement of the urethra, familiarity with landmarks during canal dissection, and rapidity of working through steps of the surgery have all dramatically improved as our experience at University of Minnesota performing primary vaginoplasty has grown,” Dr. Pariser said.

Optimal case thresholds may vary depending on a surgeon’s background, Rachel M. Whynott, MD, a reproductive endocrinology and infertility fellow at the University of Iowa in Iowa City, said in an interview. At the University of Kansas in Kansas City, a multidisciplinary team that includes a gynecologist, a reconstructive urologist, and a plastic surgeon performs the procedure.

Dr. Whynott and colleagues recently published a retrospective study that evaluated surgical aptitude over time in a male-to-female penoscrotal vaginoplasty program . Their analysis of 43 cases identified a learning curve that was reflected in overall time in the operating room and time to neoclitoral sensation.

Investigators are “trying to add to the growing body of literature about this procedure and how we can best go about improving outcomes for our patients and improving this surgery,” Dr. Whynott said. A study that includes data from multiple centers would be useful, she added.

Dr. Ferrando disclosed authorship royalties from UpToDate. Dr. Pariser and Dr. Whynott had no relevant financial disclosures.

[email protected]

SOURCE: Ferrando C. SGS 2020, Abstract 09.

Patient outcomes after gender-affirming vaginoplasty may improve as surgeons gain experience with the procedure, research suggests. For one surgeon, certain adverse events, including the need for revision surgery, were less likely after 50 cases.

“As surgical programs evolve, the important question becomes: At what case threshold are cases performed safely, efficiently, and with favorable outcomes?” said Cecile A. Ferrando, MD, MPH, program director of the female pelvic medicine and reconstructive surgery fellowship at Cleveland Clinic and director of the transgender surgery and medicine program in the Cleveland Clinic’s Center for LGBT Care.

The answer could guide training for future surgeons, Dr. Ferrando said at the virtual annual scientific meeting of the Society of Gynecologic Surgeons. Future studies should include patient-centered outcomes and data from multiple centers, other doctors said.

Transgender women who opt to surgically transition may undergo vaginoplasty. Although many reports describe surgical techniques, “there is a paucity of evidence-based data as well as few reports on outcomes,” Dr. Ferrando noted.

To describe perioperative adverse events related to vaginoplasty performed for gender affirmation and determine a minimum number of cases needed to reduce their likelihood, Dr. Ferrando performed a retrospective study of 76 patients. The patients underwent surgery between December 2015 and March 2019 and had 6-month postoperative outcomes available. Dr. Ferrando performed the procedures.

Dr. Ferrando evaluated outcomes after increments of 10 cases. After 50 cases, the median surgical time decreased to approximately 180 minutes, which an informal survey of surgeons suggested was efficient, and the rates of adverse events were similar to those in other studies. Dr. Ferrando compared outcomes from the first 50 cases with outcomes from the 26 cases that followed.

Overall, the patients had a mean age of 41 years. The first 50 patients were older on average (44 years vs. 35 years). About 83% underwent full-depth vaginoplasty. The incidence of intraoperative and immediate postoperative events was low and did not differ between the two groups. Rates of delayed postoperative events – those occurring 30 or more days after surgery – did significantly differ between the two groups, however.

After 50 cases, there was a lower incidence of urinary stream abnormalities (7.7% vs. 16.3%), introital stenosis (3.9% vs. 12%), and revision surgery (that is, elective, cosmetic, or functional revision within 6 months; 19.2% vs. 44%), compared with the first 50 cases.

The study did not include patient-centered outcomes and the results may have limited generalizability, Dr. Ferrando noted. “The incidence of serious adverse events related to vaginoplasty is low while minor events are common,” she said. “A 50-case minimum may be an adequate case number target for postgraduate trainees learning how to do this surgery.”

“I learned that the incidence of serious complications, like injuries during the surgery, or serious events immediately after surgery was quite low, which was reassuring,” Dr. Ferrando said in a later interview. “The cosmetic result and detail that is involved with the surgery – something that is very important to patients – that skill set takes time and experience to refine.”

Subsequent studies should include patient-centered outcomes, which may help surgeons understand potential “sources of consternation for patients,” such as persistent corporal tissue, poor aesthetics, vaginal stenosis, urinary meatus location, and clitoral hooding, Joseph J. Pariser, MD, commented in an interview. Dr. Pariser, a urologist who specializes in gender care at the University of Minnesota in Minneapolis, in 2019 reviewed safety outcomes from published case series.

“In my own practice, precise placement of the urethra, familiarity with landmarks during canal dissection, and rapidity of working through steps of the surgery have all dramatically improved as our experience at University of Minnesota performing primary vaginoplasty has grown,” Dr. Pariser said.

Optimal case thresholds may vary depending on a surgeon’s background, Rachel M. Whynott, MD, a reproductive endocrinology and infertility fellow at the University of Iowa in Iowa City, said in an interview. At the University of Kansas in Kansas City, a multidisciplinary team that includes a gynecologist, a reconstructive urologist, and a plastic surgeon performs the procedure.

Dr. Whynott and colleagues recently published a retrospective study that evaluated surgical aptitude over time in a male-to-female penoscrotal vaginoplasty program . Their analysis of 43 cases identified a learning curve that was reflected in overall time in the operating room and time to neoclitoral sensation.

Investigators are “trying to add to the growing body of literature about this procedure and how we can best go about improving outcomes for our patients and improving this surgery,” Dr. Whynott said. A study that includes data from multiple centers would be useful, she added.

Dr. Ferrando disclosed authorship royalties from UpToDate. Dr. Pariser and Dr. Whynott had no relevant financial disclosures.

[email protected]

SOURCE: Ferrando C. SGS 2020, Abstract 09.

Patient outcomes after gender-affirming vaginoplasty may improve as surgeons gain experience with the procedure, research suggests. For one surgeon, certain adverse events, including the need for revision surgery, were less likely after 50 cases.

“As surgical programs evolve, the important question becomes: At what case threshold are cases performed safely, efficiently, and with favorable outcomes?” said Cecile A. Ferrando, MD, MPH, program director of the female pelvic medicine and reconstructive surgery fellowship at Cleveland Clinic and director of the transgender surgery and medicine program in the Cleveland Clinic’s Center for LGBT Care.

The answer could guide training for future surgeons, Dr. Ferrando said at the virtual annual scientific meeting of the Society of Gynecologic Surgeons. Future studies should include patient-centered outcomes and data from multiple centers, other doctors said.

Transgender women who opt to surgically transition may undergo vaginoplasty. Although many reports describe surgical techniques, “there is a paucity of evidence-based data as well as few reports on outcomes,” Dr. Ferrando noted.

To describe perioperative adverse events related to vaginoplasty performed for gender affirmation and determine a minimum number of cases needed to reduce their likelihood, Dr. Ferrando performed a retrospective study of 76 patients. The patients underwent surgery between December 2015 and March 2019 and had 6-month postoperative outcomes available. Dr. Ferrando performed the procedures.

Dr. Ferrando evaluated outcomes after increments of 10 cases. After 50 cases, the median surgical time decreased to approximately 180 minutes, which an informal survey of surgeons suggested was efficient, and the rates of adverse events were similar to those in other studies. Dr. Ferrando compared outcomes from the first 50 cases with outcomes from the 26 cases that followed.

Overall, the patients had a mean age of 41 years. The first 50 patients were older on average (44 years vs. 35 years). About 83% underwent full-depth vaginoplasty. The incidence of intraoperative and immediate postoperative events was low and did not differ between the two groups. Rates of delayed postoperative events – those occurring 30 or more days after surgery – did significantly differ between the two groups, however.

After 50 cases, there was a lower incidence of urinary stream abnormalities (7.7% vs. 16.3%), introital stenosis (3.9% vs. 12%), and revision surgery (that is, elective, cosmetic, or functional revision within 6 months; 19.2% vs. 44%), compared with the first 50 cases.

The study did not include patient-centered outcomes and the results may have limited generalizability, Dr. Ferrando noted. “The incidence of serious adverse events related to vaginoplasty is low while minor events are common,” she said. “A 50-case minimum may be an adequate case number target for postgraduate trainees learning how to do this surgery.”

“I learned that the incidence of serious complications, like injuries during the surgery, or serious events immediately after surgery was quite low, which was reassuring,” Dr. Ferrando said in a later interview. “The cosmetic result and detail that is involved with the surgery – something that is very important to patients – that skill set takes time and experience to refine.”

Subsequent studies should include patient-centered outcomes, which may help surgeons understand potential “sources of consternation for patients,” such as persistent corporal tissue, poor aesthetics, vaginal stenosis, urinary meatus location, and clitoral hooding, Joseph J. Pariser, MD, commented in an interview. Dr. Pariser, a urologist who specializes in gender care at the University of Minnesota in Minneapolis, in 2019 reviewed safety outcomes from published case series.

“In my own practice, precise placement of the urethra, familiarity with landmarks during canal dissection, and rapidity of working through steps of the surgery have all dramatically improved as our experience at University of Minnesota performing primary vaginoplasty has grown,” Dr. Pariser said.

Optimal case thresholds may vary depending on a surgeon’s background, Rachel M. Whynott, MD, a reproductive endocrinology and infertility fellow at the University of Iowa in Iowa City, said in an interview. At the University of Kansas in Kansas City, a multidisciplinary team that includes a gynecologist, a reconstructive urologist, and a plastic surgeon performs the procedure.

Dr. Whynott and colleagues recently published a retrospective study that evaluated surgical aptitude over time in a male-to-female penoscrotal vaginoplasty program . Their analysis of 43 cases identified a learning curve that was reflected in overall time in the operating room and time to neoclitoral sensation.

Investigators are “trying to add to the growing body of literature about this procedure and how we can best go about improving outcomes for our patients and improving this surgery,” Dr. Whynott said. A study that includes data from multiple centers would be useful, she added.

Dr. Ferrando disclosed authorship royalties from UpToDate. Dr. Pariser and Dr. Whynott had no relevant financial disclosures.

[email protected]

SOURCE: Ferrando C. SGS 2020, Abstract 09.

A 57-year-old man living with HIV has been followed at a local infectious disease clinic for more than 15 years. He acquired HIV disease through heterosexual contact. He lives alone and works at a convenience store; he has not been sexually active for the past 5 years. He smokes 10 cigarettes a day, but does not drink alcohol or use illicit drugs. He had been on coformulated emtricitabine/tenofovir disoproxil fumarate (TDF) and coformulated lopinavir/ritonavir, which he had taken conscientiously, since May 2008, without noticing any adverse reactions from this regimen. His HIV viral load had been undetectable, and his CD4 count had hovered between 600 and 700 cells/µL. Although he was on atorvastatin for dyslipidemia, his fasting lipid profile, performed in 2018, revealed a total cholesterol level of 200 mg/dL;triglyceride, 247 mg/dL; high-density lipoprotein (HDL), 43 mg/dL; and low-density lipoprotein (LDL), 132 mg/dL. In April 2019, his HIV regimen was switched to bictegravir/emtricitabine/tenofovir alafenamide (TAF). Blood tests performed in December 2019 revealed undetectable HIV viral load; an increased CD4 count to 849 cell/µL; total cholesterol, 140 mg/dL; triglyceride, 115 mg/dL; HDL, 60 mg/dL; and LDL, 90 mg/dL.

In this case, the cliché “if it’s not broke, don’t fix it” might not hold true. This patient continued to do well, with relatively high CD4 counts and undetectable HIV viral load on the same regimen for 11 years. However, after his ART regimen was switched, his CD4 count increased further, and there was a significant improvement in his lipid profile. Smoking, HIV disease, and suboptimal lipid profile are 3 cardiovascular risk factors for this patient; the lipid profile improved by just switching the ART regimen.

In this article, we discuss simplifying and switching ART in treatment-experienced patients living with HIV across various scenarios. Currently, the International AIDS Society-USA recommends treating all patients living with HIV, regardless of CD4 count.¹ Treatment decisions should be individualized by assessing patient readiness. Other factors that must be addressed when considering simplifying or switching an ART regimen in patients whose HIV disease is well controlled virologically and who do not have drug-resistance issues are listed in Table 1.

SIMPLIFYING ART

Virologically Suppressed Patients Without Drug-Resistant Virus

Treatment adherence is of paramount importance to ensure treatment success. Patients with a viral load that is undetectable or nearly undetectable without drug resistance could be taking ART regimens consisting of more than 1 pill and/or that require more than once-daily dosing. Decreasing pill burden or dosing frequency can help to improve adherence to treatment. In addition, older-generation ART agents are usually more toxic and less potent than newer-generation agents, so another important objective of switching older drugs to newer drugs is to decrease adverse reactions and improve virologic suppression. Selection of an ART regimen should be guided by the results of resistance testing (genotyping and phenotyping tests) and previous treatment history. After switching a patient’s ART regimen, plasma HIV viral load and CD4 count should be closely monitored.² The following 3-drug, single-tablet, once-daily ART regimens can be used in patients who are virologically stable (ordered chronologically by FDA approval dates).

Efavirenz/Emtricitabine/TDF (Atripla)

Coformulated efavirenz/emtricitabine/TDF was the first single-tablet, once-daily, fixed-dose combination approved by the FDA (July 2006). Approval was based on a 48- week clinical trial involving 244 adults with HIV infection that showed that 80% of participants achieved a marked reduction in HIV viral load and a significant increase in CD4 cell count.³ Of the 3 components, efavirenz has unique central nervous system (CNS) adverse effects that could reduce adherence. Patients who were started on this fixed-dose combination commonly reported dizziness, headache, nightmare, insomnia, and impaired concentration.⁴ However, the CNS side effects resolved within the first 4 weeks of therapy, and less than 5% of patients quit taking the drug. Primate studies showed efavirenz is teratogenic, but studies in pregnant women did not find efavirenz to be more teratogenic than other ART agents.⁵

The generic version of Atripla, Symfi, is a coformulation of efavirenz/lamivudine/TDF that is considered interchangeable with Atripla. As noted, efavirenz-based ART regimens are well known for causing CNS side effects; however, the ENCORE-1 trial demonstrated that fewer side effects are noted when the standard dose of efavirenz, 600 mg, is lowered to 400 mg.⁶ Symfi Lo is an efavirenz/lamivudine/TDF single-tablet regimen that contains 400 mg of efavirenz.

Emtricitabine/Rilpivirine/TDF (Complera)

Coformulated emtricitabine/rilpivirine/TDF was approved based on data from two 48-week, phase 3, double-blind, randomized controlled trials (ECHO and THRIVE) that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naive adults with HIV infection.^7,8 Rilpivirine is well tolerated and causes fewer CNS symptoms compared to efavirenz. The main caveat for rilpivirine is drug-drug interactions. It should not be coadministered with CYP inducers, such as rifampin, phenytoin, or St. John’s wort, as coadministration can cause subtherapeutic blood levels of rilpivirine. Because increased levels of rilpivirine can prolong QTc on electrocardiogram (ECG), an ECG should be obtained before starting an ART regimen that contains rilpivirine, especially in the presence of CYP 3A4 inhibitors.⁹

Elvitegravir/Cobicistat/Emtricitabine/TDF (Stribild)

This coformulation was approved based on data from 2 randomized, double-blind, controlled trials, Study 102 and Study 103, in treatment-naive patients with HIV (n = 1408). In Study 102, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or efavirenz/emtricitabine/TDF (Atripla).¹⁰ In Study 103, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or atazanavir + ritonavir + emtricitabine/TDF. In both studies, the primary endpoint was virologic success (HIV-1 RNA < 50 copies/mL) at 48 weeks, and elvitegravir/cobicistat/emtricitabine/TDF was noninferior compared to the other regimens.¹¹

Cobicistat is needed to boost elvitegravir to therapeutic blood levels. Cobicistat is a ritonavir analogue, but has no antiretroviral activity per se. It is used exclusively as a pharmacokinetic enhancer because it is a potent CYP 3A4 inhibitor. Because cobicistat can boost the blood level of many drugs other than elvitegravir, a thorough review of the patient’s medications list should be conducted before prescribing an ART regimen that contains cobicistat to prevent serious drug-drug interactions. Because cobicistat can block transport of creatinine in the proximal tubular, a small increase in serum creatinine can be seen in some patients.¹²

Abacavir/Dolutegravir/Lamivudine (Triumeq)

Approval of abacavir/dolutegravir/lamivudine (Triumeq) in August 2014 was based on SINGLE, a noninferiority trial involving 833 treatment-naive adults that compared dolutegravir and abacavir/lamivudine (the separate components of Triumeq) to efavirenz/emtricitabine/TDF. At 96 weeks, more patients in the dolutegravir and abacavir/lamivudine arm achieved an undetectable HIV viral load (80% versus 72%).¹³

Abacavir can cause a potentially fatal hypersensitivity syndrome in susceptible patients. The syndrome is characterized by fever, malaise, maculopapular rash, and gastrointestinal complaints (eg, nausea, vomiting, anorexia, abdominal pain and diarrhea). When abacavir-induced hypersensitivity syndrome is suspected, the drug should be stopped immediately and must never be restarted. The hypersensitivity syndrome is an immune response linked to the HLA-B*5701 allele, and patients should be tested for this genetic variation before starting an ART regimen that contains abacavir.¹⁴

Elvitegravir/Cobicistat/Emtricitabine/TAF (Genvoya)

Approval of coformulated elvitegravir/cobicistat/emtricitabine/TAF was supported by data from two 48-week phase 3, double-blind studies (Studies 104 and 111) involving 1733 treatment-naive patients that compared the regimen to elvitegravir/cobicistat/emtricitabine/TDF (Stribild). Both studies demonstrated that elvitegravir/cobicistat/emtricitabine/TAF was statistically noninferior, and it was favored in regard to certain renal and bone laboratory parameters.¹⁵ Studies comparing TAF and TDF have demonstrated that TAF is less likely to cause loss of bone mineral density and nephrotoxicity compared to TDF.^16,17

Emtricitabine/Rilpivirine/TAF (Odefsey)

Coformulated emtricitabine/rilpivirine/TAF was approved based, in part, on positive bioequivalence studies demonstrating that it achieved similar drug levels of emtricitabine and TAF as coformulated elvitegravir/cobicistat/emtricitabine/TAF and similar drug levels of rilpivirine as individually dosed rilpivirine.¹⁸ The safety, efficacy, and tolerability of this coformulation is supported by clinical studies of rilpivirine-based therapy and emtricitabine/TAF-based therapy in a range of patients with HIV.¹⁸

Bictegravir/Emtricitabine/TAF (Biktarvy)

The coformulation bictegravir/emtricitabine/TAF was approved based on 4 phase 3 studies: Studies 1489 and 1490 in treatment-naive adults, and Studies 1844 and 1878 in virologically suppressed adults. In Study 1489, 629 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or coformulated abacavir/dolutegravir/lamivudine. At week 48, similar percentages of patients in each arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL. In Study 1490, 645 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or dolutegravir + emtricitabine/TAF. At week 48, similar percentages of patients in each arm achieved the primary endpoint of virologic success (HIV-1 RNA < 50 copies/mL).^19,20

Bictegravir is used in Biktarvy in place of the elvitegravir/cobicistat combination used in Genvoya. This non-cobicistat regimen has the advantage of having a lower risk of serious drug-drug interactions.

Darunavir/Cobicistat/Emtricitabine/TAF (Symtuza)

Approval of coformulated darunavir/cobicistat/emtricitabine/TAF was based on data from two 48-week, noninferiority, phase 3 studies that assessed the safety and efficacy of the coformulation versus a control regimen (darunavir/cobicistat plus emtricitabine/TDF) in adults with no prior ART history (AMBER) and in virologically suppressed adults (EMERALD). In the randomized, double-blind, multicenter controlled AMBER trial, at week 48, 91.4% of patients in the study group and 88.4% in the control group achieved viral suppression (HIV-1 RNA < 50 copies/mL), and virologic failure rates were low in both groups (HIV-1 RNA ≥ 50 copies/mL; 4.4% versus 3.3%, respectively).²¹

The randomized, double-blind, multicenter controlled EMERALD trial compared coformulated darunavir/cobicistat/emtricitabine/TAF to continuing a boosted PI plus emtricitabine and TDF in virologically suppressed patients who were already on a boosted PI–based regimen. At week 48, 2.5% of patients on coformulated darunavir/cobicistat/emtricitabine/TAF versus 2.1% on the control regimen had rebound HIV-1 RNA ≥ 50 copies/mL, and high virologic suppression rates were observed in both groups (HIV-1 RNA < 50 copies/mL: 94.9% versus 93.7%, respectively).²²

Doravirine/Lamivudine/TDF (Delstrigo)

Coformulated doravirine/lamivudine/TDF was approved based on data from 2 randomized, double-blind, controlled phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD. The former trial compared coformulated doravirine/lamivudine/TDF with efavirenz/emtricitabine/TDF in 728 treatment-naive patients. At 48 weeks, 84.3% in the doravirine/lamivudine/TDF arm and 80.8% in the efavirenz/emtricitabine/TDF arm met the primary endpoint of HIV-1 RNA < 50 copies/mL. Thus, doravirine/lamivudine/TDF showed sustained viral suppression and noninferiority compared to efavirenz/emtricitabine/TDF.²³ The DRIVE-FORWARD trial investigated doravirine compared with ritonavir-boosted darunavir, each in combination with 2 NRTIs (TDF with emtricitabine or abacavir with lamivudine). At week 48, 84% of patients in the doravirine arm and 80% in the ritonavir-boosted darunavir arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL.²⁴

Two-Drug, Single-Tablet, Once-Daily Regimens

Experts have long recommended that optimal treatment of HIV must consist of 3 active drugs, with trials both in the United States and Europe demonstrating decreased morbidity and mortality with 3-drug therapy.^25,26 However, newer, more potent 2-drug therapy is giving more choices to people living with HIV. The single-tablet, 2-drug regimens currently available are dolutegravir/rilpivirine and dolutegravir/lamivudine. There are theoretical benefits of 2-drug therapy, such as minimizing long-term toxicities, avoidance of some drug-drug interactions, and preservation of drugs for future treatment options. At this time, a 2-drug simplification regimen can be a viable option for selected virologically stable populations.

Dolutegravir/Rilpivirine (Juluca)

Dolutegravir/rilpivirine has been shown to be noninferior to standard therapy at 48-weeks, although it is associated with a higher discontinuation rate because of side effects.²⁷ This option can be particularly useful in patients who have contraindications to NRTIs or renal dysfunction, but it has been studied only in patients without resistance who are already virologically suppressed. Ongoing studies are looking at 2-versus 3-drug therapies for HIV treatment-experienced patients. Most of these use PIs as a backbone because of their potency and high barrier to resistance. The advent of second-generation integrase inhibitors offers additional options.

Dolutegravir/Lamivudine (Dovato)

The GEMINI-1 and GEMINI-2 trials demonstrated that dolutegravir/lamivudine was noninferior to dolutegravir/TDF/emtricitabine.²⁸ Based on these 2 studies, new guidelines have added dolutegravir/lamivudine as a recommended first-line therapy. For now, the recommendation is to use dolutegravir/lamivudine in individuals where NRTIs are contraindicated, and it should not be used in patients with chronic hepatitis B. Additionally, 3 studies have demonstrated the safety and efficacy of switching to dolutegravir/lamivudine.^29-31 In the TANGO trial, neither virologic failures nor resistant virus were identified at 48 weeks following the switch.³² Although there are benefits of simplification with this regimen, including lower toxicity, lower costs, and saving other NRTIs in case of resistance, there should be no rush to switch patients to a 2-drug regimen. This is a viable strategy in patients without baseline resistance who have preserved T-cells and do not have hepatitis B.

SWITCHING ART AGENTS IN SELECTED CLINICAL SCENARIOS

Virologic Failure

One of the main goals of ART is maximal and durable suppression of HIV viral load to prevent the development of drug-resistant mutations.² When patients are unable to achieve durable virologic suppression or have virologic rebound, the cause of virologic failure needs to be investigated. Virologic failure is defined as the inability to achieve or maintain viral suppression to a level below 200 copies/mL, whereas rebound is defined as an HIV RNA level exceeding 200 copies/mL after virologic suppression.³³ A common cause of virologic failure is patient nonadherence, which can be related to a range of factors, including psychosocial issues and affordability of medications. Innate viral resistance can be the result of transmitted drug resistance at the time of infection or be acquired during unsuppressed viral replication secondary to inherent error-prone reverse transcriptase.³³ Pharmacokinetic factors that affect blood levels of ART, such as drug-drug interactions, also can be a key factor in HIV drug resistance.

Clinical decisions regarding patients with virologic failure are based on baseline viral load and results from genotypic resistance assays. These assays are routinely done to identify mutations associated with drug resistance. Standard resistance testing is carried out when the viral load exceeds 1000 copies/mL, but it should be attempted when the viral load is greater than 500 copies/mL.² Furthermore, testing should be done while the patient is on ART or within 4 weeks of discontinuing treatment. Although a genotype assay may be done more than 4 weeks after stopping therapy, detectability of major mutations declines rapidly.³⁴ Stanford University offers an online public database of HIV drug resistance data (https://hivdb.stanford.edu/pages/genotype-rx.html).

Those who have a baseline viral load greater than the lower limit of detection, but consistently less than 200 copies/mL, are considered at low risk for subsequent development of viral resistance, and therefore do not routinely require a change in ART.³⁵ When viral loads are between 200 and 1000 copies/mL, efforts should be made to obtain a genotype, especially if the viral load exceeds 500 copies/mL; management of these patients is the same as management for those with a viral load exceeding 1000 copies/mL. When the viral load is too low to obtain a resistance assay, empiric changes to ART should be done on a case-by-case basis.² In these cases, if no empiric changes are made, repeat viral load testing is recommended and genotype testing can be performed once the viral load exceeds 500 copies/mL.

Management of patients with a viral load exceeding 1000 copies/mL is guided by the results of genotype testing. If resistance is not found, then ongoing counseling for adherence and/or determining whether there are drug-drug or drug-food interactions causing suboptimal drug levels are recommended. For patients with drug-resistant virus, current guidelines recommend that the new regimen should contain at least2, preferably 3, fully active drugs; moreover, these drugs should be based on drug resistance characteristics and, ideally, different mechanisms of action.² Any change should also take into account other medical conditions, such as hepatitis B, coronary artery disease, chronic kidney disease, and pregnancy status.

The goal of changing ART should be re-suppression, whenever possible. Designing a new regimen following failure of the primary regimen is based on the general principles listed in Table 2.

Patients With Limited Treatment Options

Despite advances in ART, some patients exhaust the existing regimens, leading to development of multidrug resistance and limited treatment options. In light of the treatment challenges in this group of patients, the FDA has recently approved 2 antiretroviral agents to target multidrug-resistant HIV: ibalizumab and fostemsavir.

Ibalizumab is a humanized IgG4 monoclonal antibody that blocks the entry of HIV through noncompetitive binding to the primary receptor of CD4 cells. It is used for the treatment of HIV infection in heavily treatment-
experienced patients with multidrug-resistant advanced HIV infection who are failing their current ART regimen. Ibalizumab is administered intravenously once a week.

Ibalizumab was studied in a multicenter, open-label, phase 3 trial that enrolled 40 adults in whom multiple ART regimens failed because of multidrug-resistant HIV infection. All the patients had a viral load of more than 1000 copies/mL. Patients received a loading dose of 2000 mg of ibalizumab with their current failing regimen for 1 week, and then received 800 mg of ibalizumab every 14 days, combined with an optimized treatment regimen for 6 months. After 1 week of ibalizumab therapy, 83% of the patients experienced a decrease in viral load. After 6 months, 43% had a viral load of less than 50 copies/mL, and 50% had a viral load of less than 200 copies/mL.³⁶

Fostemsavir is the prodrug of temsavir, a first-in-class HIV-1 attachment inhibitor. It is used in patients with HIV disease who lack treatment options because of multidrug resistance or intolerance to other drugs. It is an oral drug to be taken twice a day. Fostemsavir was studied in 371 heavily treatment-experienced patients with multidrug-resistant HIV infection across 23 countries, with 272 patients undergoing treatment in the main randomized cohort (BRIGHTE trial). Patients in the main cohort received either fostemsavir or placebo twice daily for 8 days, in addition to their failing ART regimen. The remaining 99 patients received fostemsavir in a second nonrandomized cohort. Patients in the second cohort who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1. At week 48, 54% of the randomized group and 38% of the nonrandomized group achieved undetectable HIV viral loads (HIV RNA level < 40 copies/mL).³⁷

Pregnancy

ART is used during pregnancy to maintain the pregnant woman’s health and to prevent perinatal transmission. Pregnancy can present unique challenges to effective ART, and therapy decisions should be made based on short-term and long-term safety data, pharmacokinetics, and tolerability. With few exceptions, women who are on a stable ART regimen and present for care should continue the same regimen.³⁸ Key exceptions, due to increased toxicity, include didanosine, indinavir, nelfinavir, stavudine, and treatment-dose ritonavir. Cobicistat-based regimens (atazanavir, darunavir, elvitegravir) have altered pharmacokinetics during the second and third trimesters of pregnancy, leading to reduced mean steady-state minimum concentrations.³⁹ Because increasing plasma HIV RNA level is associated with transmission to infants, women continuing cobicistat-based ART treatments should undergo more frequent viral load measurements.⁴⁰ If viral rebound occurs late in pregnancy, especially shortly before delivery, achieving viral suppression can be more difficult. Therefore, women on a suppressed ART regimen containing cobicistat should consider switching to a different recommended regimen.³⁸

Both darunavir and atazanavir are considered preferred PI regimens in pregnancy. Darunavir’s median area under the concentration-time curve (AUC) is decreased by 38% and 39% in the second and third trimesters, respectively.⁴¹ During pregnancy, twice daily administration of darunavir/ritonavir 600 mg/100 mg is recommended. The pharmacokinetics of using twice-daily 800-mg darunavir is not supported and therefore not recommended.⁴² Similarly, the atazanavir AUC was 30% lower during the third trimester when atazanavir/ritonavir was used with TDF.⁴³ The package insert recommends using an increased dose of atazanavir/ritonavir (400 mg/100 mg) during pregnancy when used concomitantly with TDF or an H2-receptor blocker. Heartburn during pregnancy is common, and H2 blockers and proton pump inhibitors are considered safe during pregnancy, but are associated with drug-drug interactions.

Of the alternative regimens, rilpivirine-based regimens show highly variable pharmacokinetics during pregnancy, with AUC and trough concentrations between 20% and 50% lower.⁴⁴ While there is not sufficient data to recommend a change in dosing, women on rilpivirine-based regimens should have closer monitoring of HIV viral loads. Preliminary data from the Tsepamo Study, a birth surveillance study, suggested there is a higher risk of neural tube defects in children of women receiving dolutegravir. This led the World Health Organization and US Department of Health and Human Services to avoid using dolutegravir. Further follow-up showed that, although the risk is slightly higher, the difference is an additional 2 neural tube defects for every 1000 women exposed to the drug. However, dolutegravir offers great benefits, and thus the latest panel guidelines recommend use of dolutegravir as a preferred ART drug.⁴⁵

Geriatric Populations

Although HIV is seen predominantly in younger patients, 48% of persons living with HIV are older than 50 years and 8% are 65 years of age or older.⁴⁶ With effective antiretroviral treatment, we will continue to see an aging population of people living with HIV. There are no specific guidelines regarding the treatment of older adults, but HIV treatment can have its own challenges. Physiologic declines in renal function occur with aging, which can be compounded by an increasing prevalence of diabetes and decreased muscle mass, making estimations of renal function unreliable.⁴⁷ Physiologic changes with age, such as decline in renal and hepatic function, decreasing metabolism via cytochrome P450, and body composition, influence drug pharmacokinetics and can in turn potentiate drug toxicities.⁴⁸ Comorbid states and polypharmacy can complicate care. The prevalence of polypharmacy in the elderly is high, 93%, and is increasing.^49,50 A study found that in those aged 65 years or older with HIV, 65% had at least 1 potential drug-drug interaction, and 6.6% had a potential severe drug-drug interaction.⁵⁰ These patients are thus at risk of poor drug adherence, which in HIV therapy can lead to rebound viremia and resistance.

Optimizing ART in older adults also needs to account for greater comorbidities. For individuals at risk of osteopenia or osteoporosis, expert guidance suggests a benefit from regimens that spare the use of TDF or boosted PIs.⁵¹ Similarly, exposure to TDF and atazanavir has been suggested as potentially nephrotoxic, and avoiding these regimens in older patients should be considered.⁵²

Renal Insufficiency

Several commonly used ART agents have nephrotoxic potential. The most common manifestations of nephrotoxicity are tubular toxicity, crystal nephropathy, and interstitial nephritis. Of these, acute tubular toxicity caused by TDF is the most widely reported. About 2% of those taking TDF developed treatment-limiting renal insufficiency, manifested as Fanconi syndrome.⁵³ Higher plasma levels of TDF are associated with increased nephrotoxicity.⁵⁵ Guidelines recommend switching from TDF if the estimated glomerular filtration rate (eGFR) declines by > 25% or the eGFr is < 60/mL/min/1.73 m². Wever et al reports that in TDF-associated nephrotoxicity, only 42% of patients reached their pre-TDF eGFR.⁵⁴TAF, a prodrug of TDF, is associated with reduced levels of TDF and is hypothesized to have fewer adverse effects.⁵⁵ A pooled analysis comparing renal adverse effects of TDF and TAF reported no cases of renal dysfunction in the TAF group, supporting its safety; however, acute kidney injury has also been reported with TAF.^56,57 Switching from TDF to TAF in patients with renal dysfunction has been shown to lead to improvement in proteinuria, but the impact remains unclear.⁵³

Rarely, crystal nephropathy and interstitial nephritis are associated with indinavir and atazanavir therapy, which can progress to glomerulonephritis if not recognized.⁵⁹ Transitioning to another PI or INSTI is an appropriate strategy. It should be noted that dolutegravir, raltegravir, and the pharmacokinetic enhancer cobicistat increase serum creatinine up to 0.2 mg/dL via altered proximal tubular secretion of creatinine, but do not affect the actual GFR, and thus no medication adjustment is necessary.⁶⁰ If kidney injury is secondary to intrinsic nephrotoxic effects of ART, switching ART may be required.

Dyslipidemia and Cardiovascular Risk

Aside from the traditional cardiovascular risks, PIs, TAF, and efavirenz can negatively affect the lipid profile, with changes in LDL and triglycerides appearing as early as 2 weeks after initiating therapy. An observational study from Spain showed that treatment with TAF worsens the lipid profile in comparison to patients treated with TDF for elvitegravir/cobicistat-based therapies; patients on TAF were twice as likely to need lipid-lower drugs in comparison to those in the TDF arm.⁶¹ Similarly, patients who changed from a TDF-based regimen to TAF for improved renal and bone safety profiles had significant changes in both total cholesterol and LDL.⁶⁵Other NRTIs do not negatively affect lipid profile. Although NNRTIs can increase LDL, this is usually offset by an increase in HDL.⁶² Of the NNRTIs, the incidence of increased LDL is higher with efavirenz, but it also can cause an increase in HDL; in contrast, patients switched from efavirenz to rilpivirine have a better lipid profile.^63,64 PIs, especially older ones such as lopinavir/ritonavir, are associated with lipid abnormalities. For patients who develop dyslipidemia as a result of using older PIs, switching to a darunavir or atazanavir regimen or even integrase inhibitors, which are considered lipid neutral, is recommended.⁶³ When making adjustments in ART, care should be taken in prescribing abacavir to individuals with risk factors for coronary artery disease. Although there is no consensus, some randomized controlled trials suggested an association between myocardial infarction and abacavir, whereas others have not.^66,67

Because cardiovascular disease is a leading cause of death among people living with HIV, clinicians should remain mindful of the risks posed by some antiretroviral agents and consider use of lipid-neutral agents and modification of risk factors.

HIV and Hepatis B Co-infection

In patients with HIV and hepatitis B co-infection, ART regimens should contain 1 drug that is active against hepatitis B (lamivudine, emtricitabine, TDF, or TAF). Clinicians should monitor liver function for hepatitis B reactivation and liver function when a regimen that contains anti-hepatitis B drugs is stopped because discontinuation of these regimens can result in acute, and sometimes fatal, liver damage.²

Financial Considerations

With out-of-pocket expenses and co-pays, some patients may have to switch ART regimens for financial reasons. Additionally, switching to generic versions of ART has been proposed as a means of saving resources for government programs already facing budgetary constraints. A study published in 2013 using generic-based ART versus branded ART showed a potential savings of almost $1 billion per year.⁶⁸ A key barrier to the use of generic-based ART is patient skepticism regarding the performance of these medications. Branded ART regimens are also co-formulated, creating the perception that taking more pills will lead to noncompliance and therefore place the patient at risk of viral rebound. In a study from France, only 17% of patients were willing to switch to generic medications if doing so increased pill burden.⁶⁹ In the same study, 75% physicians were generally willing to prescribe generics; however, that number dropped to 26% if the patient’s pill burden would increase.⁶⁹ Paradoxically, because of the patchwork of insurance, government assistance, Medicaid, and Medicare, changing to generic-based ART may increase patients’ co-pays.

A 57-year-old man living with HIV has been followed at a local infectious disease clinic for more than 15 years. He acquired HIV disease through heterosexual contact. He lives alone and works at a convenience store; he has not been sexually active for the past 5 years. He smokes 10 cigarettes a day, but does not drink alcohol or use illicit drugs. He had been on coformulated emtricitabine/tenofovir disoproxil fumarate (TDF) and coformulated lopinavir/ritonavir, which he had taken conscientiously, since May 2008, without noticing any adverse reactions from this regimen. His HIV viral load had been undetectable, and his CD4 count had hovered between 600 and 700 cells/µL. Although he was on atorvastatin for dyslipidemia, his fasting lipid profile, performed in 2018, revealed a total cholesterol level of 200 mg/dL;triglyceride, 247 mg/dL; high-density lipoprotein (HDL), 43 mg/dL; and low-density lipoprotein (LDL), 132 mg/dL. In April 2019, his HIV regimen was switched to bictegravir/emtricitabine/tenofovir alafenamide (TAF). Blood tests performed in December 2019 revealed undetectable HIV viral load; an increased CD4 count to 849 cell/µL; total cholesterol, 140 mg/dL; triglyceride, 115 mg/dL; HDL, 60 mg/dL; and LDL, 90 mg/dL.

In this case, the cliché “if it’s not broke, don’t fix it” might not hold true. This patient continued to do well, with relatively high CD4 counts and undetectable HIV viral load on the same regimen for 11 years. However, after his ART regimen was switched, his CD4 count increased further, and there was a significant improvement in his lipid profile. Smoking, HIV disease, and suboptimal lipid profile are 3 cardiovascular risk factors for this patient; the lipid profile improved by just switching the ART regimen.

In this article, we discuss simplifying and switching ART in treatment-experienced patients living with HIV across various scenarios. Currently, the International AIDS Society-USA recommends treating all patients living with HIV, regardless of CD4 count.¹ Treatment decisions should be individualized by assessing patient readiness. Other factors that must be addressed when considering simplifying or switching an ART regimen in patients whose HIV disease is well controlled virologically and who do not have drug-resistance issues are listed in Table 1.

SIMPLIFYING ART

Virologically Suppressed Patients Without Drug-Resistant Virus

Treatment adherence is of paramount importance to ensure treatment success. Patients with a viral load that is undetectable or nearly undetectable without drug resistance could be taking ART regimens consisting of more than 1 pill and/or that require more than once-daily dosing. Decreasing pill burden or dosing frequency can help to improve adherence to treatment. In addition, older-generation ART agents are usually more toxic and less potent than newer-generation agents, so another important objective of switching older drugs to newer drugs is to decrease adverse reactions and improve virologic suppression. Selection of an ART regimen should be guided by the results of resistance testing (genotyping and phenotyping tests) and previous treatment history. After switching a patient’s ART regimen, plasma HIV viral load and CD4 count should be closely monitored.² The following 3-drug, single-tablet, once-daily ART regimens can be used in patients who are virologically stable (ordered chronologically by FDA approval dates).

Efavirenz/Emtricitabine/TDF (Atripla)

Coformulated efavirenz/emtricitabine/TDF was the first single-tablet, once-daily, fixed-dose combination approved by the FDA (July 2006). Approval was based on a 48- week clinical trial involving 244 adults with HIV infection that showed that 80% of participants achieved a marked reduction in HIV viral load and a significant increase in CD4 cell count.³ Of the 3 components, efavirenz has unique central nervous system (CNS) adverse effects that could reduce adherence. Patients who were started on this fixed-dose combination commonly reported dizziness, headache, nightmare, insomnia, and impaired concentration.⁴ However, the CNS side effects resolved within the first 4 weeks of therapy, and less than 5% of patients quit taking the drug. Primate studies showed efavirenz is teratogenic, but studies in pregnant women did not find efavirenz to be more teratogenic than other ART agents.⁵

The generic version of Atripla, Symfi, is a coformulation of efavirenz/lamivudine/TDF that is considered interchangeable with Atripla. As noted, efavirenz-based ART regimens are well known for causing CNS side effects; however, the ENCORE-1 trial demonstrated that fewer side effects are noted when the standard dose of efavirenz, 600 mg, is lowered to 400 mg.⁶ Symfi Lo is an efavirenz/lamivudine/TDF single-tablet regimen that contains 400 mg of efavirenz.

Emtricitabine/Rilpivirine/TDF (Complera)

Coformulated emtricitabine/rilpivirine/TDF was approved based on data from two 48-week, phase 3, double-blind, randomized controlled trials (ECHO and THRIVE) that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naive adults with HIV infection.^7,8 Rilpivirine is well tolerated and causes fewer CNS symptoms compared to efavirenz. The main caveat for rilpivirine is drug-drug interactions. It should not be coadministered with CYP inducers, such as rifampin, phenytoin, or St. John’s wort, as coadministration can cause subtherapeutic blood levels of rilpivirine. Because increased levels of rilpivirine can prolong QTc on electrocardiogram (ECG), an ECG should be obtained before starting an ART regimen that contains rilpivirine, especially in the presence of CYP 3A4 inhibitors.⁹

Elvitegravir/Cobicistat/Emtricitabine/TDF (Stribild)

This coformulation was approved based on data from 2 randomized, double-blind, controlled trials, Study 102 and Study 103, in treatment-naive patients with HIV (n = 1408). In Study 102, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or efavirenz/emtricitabine/TDF (Atripla).¹⁰ In Study 103, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or atazanavir + ritonavir + emtricitabine/TDF. In both studies, the primary endpoint was virologic success (HIV-1 RNA < 50 copies/mL) at 48 weeks, and elvitegravir/cobicistat/emtricitabine/TDF was noninferior compared to the other regimens.¹¹

Cobicistat is needed to boost elvitegravir to therapeutic blood levels. Cobicistat is a ritonavir analogue, but has no antiretroviral activity per se. It is used exclusively as a pharmacokinetic enhancer because it is a potent CYP 3A4 inhibitor. Because cobicistat can boost the blood level of many drugs other than elvitegravir, a thorough review of the patient’s medications list should be conducted before prescribing an ART regimen that contains cobicistat to prevent serious drug-drug interactions. Because cobicistat can block transport of creatinine in the proximal tubular, a small increase in serum creatinine can be seen in some patients.¹²

Abacavir/Dolutegravir/Lamivudine (Triumeq)

Approval of abacavir/dolutegravir/lamivudine (Triumeq) in August 2014 was based on SINGLE, a noninferiority trial involving 833 treatment-naive adults that compared dolutegravir and abacavir/lamivudine (the separate components of Triumeq) to efavirenz/emtricitabine/TDF. At 96 weeks, more patients in the dolutegravir and abacavir/lamivudine arm achieved an undetectable HIV viral load (80% versus 72%).¹³

Abacavir can cause a potentially fatal hypersensitivity syndrome in susceptible patients. The syndrome is characterized by fever, malaise, maculopapular rash, and gastrointestinal complaints (eg, nausea, vomiting, anorexia, abdominal pain and diarrhea). When abacavir-induced hypersensitivity syndrome is suspected, the drug should be stopped immediately and must never be restarted. The hypersensitivity syndrome is an immune response linked to the HLA-B*5701 allele, and patients should be tested for this genetic variation before starting an ART regimen that contains abacavir.¹⁴

Elvitegravir/Cobicistat/Emtricitabine/TAF (Genvoya)

Approval of coformulated elvitegravir/cobicistat/emtricitabine/TAF was supported by data from two 48-week phase 3, double-blind studies (Studies 104 and 111) involving 1733 treatment-naive patients that compared the regimen to elvitegravir/cobicistat/emtricitabine/TDF (Stribild). Both studies demonstrated that elvitegravir/cobicistat/emtricitabine/TAF was statistically noninferior, and it was favored in regard to certain renal and bone laboratory parameters.¹⁵ Studies comparing TAF and TDF have demonstrated that TAF is less likely to cause loss of bone mineral density and nephrotoxicity compared to TDF.^16,17

Emtricitabine/Rilpivirine/TAF (Odefsey)

Coformulated emtricitabine/rilpivirine/TAF was approved based, in part, on positive bioequivalence studies demonstrating that it achieved similar drug levels of emtricitabine and TAF as coformulated elvitegravir/cobicistat/emtricitabine/TAF and similar drug levels of rilpivirine as individually dosed rilpivirine.¹⁸ The safety, efficacy, and tolerability of this coformulation is supported by clinical studies of rilpivirine-based therapy and emtricitabine/TAF-based therapy in a range of patients with HIV.¹⁸

Bictegravir/Emtricitabine/TAF (Biktarvy)

The coformulation bictegravir/emtricitabine/TAF was approved based on 4 phase 3 studies: Studies 1489 and 1490 in treatment-naive adults, and Studies 1844 and 1878 in virologically suppressed adults. In Study 1489, 629 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or coformulated abacavir/dolutegravir/lamivudine. At week 48, similar percentages of patients in each arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL. In Study 1490, 645 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or dolutegravir + emtricitabine/TAF. At week 48, similar percentages of patients in each arm achieved the primary endpoint of virologic success (HIV-1 RNA < 50 copies/mL).^19,20

Bictegravir is used in Biktarvy in place of the elvitegravir/cobicistat combination used in Genvoya. This non-cobicistat regimen has the advantage of having a lower risk of serious drug-drug interactions.

Darunavir/Cobicistat/Emtricitabine/TAF (Symtuza)

Approval of coformulated darunavir/cobicistat/emtricitabine/TAF was based on data from two 48-week, noninferiority, phase 3 studies that assessed the safety and efficacy of the coformulation versus a control regimen (darunavir/cobicistat plus emtricitabine/TDF) in adults with no prior ART history (AMBER) and in virologically suppressed adults (EMERALD). In the randomized, double-blind, multicenter controlled AMBER trial, at week 48, 91.4% of patients in the study group and 88.4% in the control group achieved viral suppression (HIV-1 RNA < 50 copies/mL), and virologic failure rates were low in both groups (HIV-1 RNA ≥ 50 copies/mL; 4.4% versus 3.3%, respectively).²¹

The randomized, double-blind, multicenter controlled EMERALD trial compared coformulated darunavir/cobicistat/emtricitabine/TAF to continuing a boosted PI plus emtricitabine and TDF in virologically suppressed patients who were already on a boosted PI–based regimen. At week 48, 2.5% of patients on coformulated darunavir/cobicistat/emtricitabine/TAF versus 2.1% on the control regimen had rebound HIV-1 RNA ≥ 50 copies/mL, and high virologic suppression rates were observed in both groups (HIV-1 RNA < 50 copies/mL: 94.9% versus 93.7%, respectively).²²

Doravirine/Lamivudine/TDF (Delstrigo)

Coformulated doravirine/lamivudine/TDF was approved based on data from 2 randomized, double-blind, controlled phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD. The former trial compared coformulated doravirine/lamivudine/TDF with efavirenz/emtricitabine/TDF in 728 treatment-naive patients. At 48 weeks, 84.3% in the doravirine/lamivudine/TDF arm and 80.8% in the efavirenz/emtricitabine/TDF arm met the primary endpoint of HIV-1 RNA < 50 copies/mL. Thus, doravirine/lamivudine/TDF showed sustained viral suppression and noninferiority compared to efavirenz/emtricitabine/TDF.²³ The DRIVE-FORWARD trial investigated doravirine compared with ritonavir-boosted darunavir, each in combination with 2 NRTIs (TDF with emtricitabine or abacavir with lamivudine). At week 48, 84% of patients in the doravirine arm and 80% in the ritonavir-boosted darunavir arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL.²⁴

Two-Drug, Single-Tablet, Once-Daily Regimens

Experts have long recommended that optimal treatment of HIV must consist of 3 active drugs, with trials both in the United States and Europe demonstrating decreased morbidity and mortality with 3-drug therapy.^25,26 However, newer, more potent 2-drug therapy is giving more choices to people living with HIV. The single-tablet, 2-drug regimens currently available are dolutegravir/rilpivirine and dolutegravir/lamivudine. There are theoretical benefits of 2-drug therapy, such as minimizing long-term toxicities, avoidance of some drug-drug interactions, and preservation of drugs for future treatment options. At this time, a 2-drug simplification regimen can be a viable option for selected virologically stable populations.

Dolutegravir/Rilpivirine (Juluca)

Dolutegravir/rilpivirine has been shown to be noninferior to standard therapy at 48-weeks, although it is associated with a higher discontinuation rate because of side effects.²⁷ This option can be particularly useful in patients who have contraindications to NRTIs or renal dysfunction, but it has been studied only in patients without resistance who are already virologically suppressed. Ongoing studies are looking at 2-versus 3-drug therapies for HIV treatment-experienced patients. Most of these use PIs as a backbone because of their potency and high barrier to resistance. The advent of second-generation integrase inhibitors offers additional options.

Dolutegravir/Lamivudine (Dovato)

The GEMINI-1 and GEMINI-2 trials demonstrated that dolutegravir/lamivudine was noninferior to dolutegravir/TDF/emtricitabine.²⁸ Based on these 2 studies, new guidelines have added dolutegravir/lamivudine as a recommended first-line therapy. For now, the recommendation is to use dolutegravir/lamivudine in individuals where NRTIs are contraindicated, and it should not be used in patients with chronic hepatitis B. Additionally, 3 studies have demonstrated the safety and efficacy of switching to dolutegravir/lamivudine.^29-31 In the TANGO trial, neither virologic failures nor resistant virus were identified at 48 weeks following the switch.³² Although there are benefits of simplification with this regimen, including lower toxicity, lower costs, and saving other NRTIs in case of resistance, there should be no rush to switch patients to a 2-drug regimen. This is a viable strategy in patients without baseline resistance who have preserved T-cells and do not have hepatitis B.

SWITCHING ART AGENTS IN SELECTED CLINICAL SCENARIOS

Virologic Failure

One of the main goals of ART is maximal and durable suppression of HIV viral load to prevent the development of drug-resistant mutations.² When patients are unable to achieve durable virologic suppression or have virologic rebound, the cause of virologic failure needs to be investigated. Virologic failure is defined as the inability to achieve or maintain viral suppression to a level below 200 copies/mL, whereas rebound is defined as an HIV RNA level exceeding 200 copies/mL after virologic suppression.³³ A common cause of virologic failure is patient nonadherence, which can be related to a range of factors, including psychosocial issues and affordability of medications. Innate viral resistance can be the result of transmitted drug resistance at the time of infection or be acquired during unsuppressed viral replication secondary to inherent error-prone reverse transcriptase.³³ Pharmacokinetic factors that affect blood levels of ART, such as drug-drug interactions, also can be a key factor in HIV drug resistance.

Clinical decisions regarding patients with virologic failure are based on baseline viral load and results from genotypic resistance assays. These assays are routinely done to identify mutations associated with drug resistance. Standard resistance testing is carried out when the viral load exceeds 1000 copies/mL, but it should be attempted when the viral load is greater than 500 copies/mL.² Furthermore, testing should be done while the patient is on ART or within 4 weeks of discontinuing treatment. Although a genotype assay may be done more than 4 weeks after stopping therapy, detectability of major mutations declines rapidly.³⁴ Stanford University offers an online public database of HIV drug resistance data (https://hivdb.stanford.edu/pages/genotype-rx.html).

Those who have a baseline viral load greater than the lower limit of detection, but consistently less than 200 copies/mL, are considered at low risk for subsequent development of viral resistance, and therefore do not routinely require a change in ART.³⁵ When viral loads are between 200 and 1000 copies/mL, efforts should be made to obtain a genotype, especially if the viral load exceeds 500 copies/mL; management of these patients is the same as management for those with a viral load exceeding 1000 copies/mL. When the viral load is too low to obtain a resistance assay, empiric changes to ART should be done on a case-by-case basis.² In these cases, if no empiric changes are made, repeat viral load testing is recommended and genotype testing can be performed once the viral load exceeds 500 copies/mL.

Management of patients with a viral load exceeding 1000 copies/mL is guided by the results of genotype testing. If resistance is not found, then ongoing counseling for adherence and/or determining whether there are drug-drug or drug-food interactions causing suboptimal drug levels are recommended. For patients with drug-resistant virus, current guidelines recommend that the new regimen should contain at least2, preferably 3, fully active drugs; moreover, these drugs should be based on drug resistance characteristics and, ideally, different mechanisms of action.² Any change should also take into account other medical conditions, such as hepatitis B, coronary artery disease, chronic kidney disease, and pregnancy status.

The goal of changing ART should be re-suppression, whenever possible. Designing a new regimen following failure of the primary regimen is based on the general principles listed in Table 2.

Patients With Limited Treatment Options

Despite advances in ART, some patients exhaust the existing regimens, leading to development of multidrug resistance and limited treatment options. In light of the treatment challenges in this group of patients, the FDA has recently approved 2 antiretroviral agents to target multidrug-resistant HIV: ibalizumab and fostemsavir.

Ibalizumab is a humanized IgG4 monoclonal antibody that blocks the entry of HIV through noncompetitive binding to the primary receptor of CD4 cells. It is used for the treatment of HIV infection in heavily treatment-
experienced patients with multidrug-resistant advanced HIV infection who are failing their current ART regimen. Ibalizumab is administered intravenously once a week.

Ibalizumab was studied in a multicenter, open-label, phase 3 trial that enrolled 40 adults in whom multiple ART regimens failed because of multidrug-resistant HIV infection. All the patients had a viral load of more than 1000 copies/mL. Patients received a loading dose of 2000 mg of ibalizumab with their current failing regimen for 1 week, and then received 800 mg of ibalizumab every 14 days, combined with an optimized treatment regimen for 6 months. After 1 week of ibalizumab therapy, 83% of the patients experienced a decrease in viral load. After 6 months, 43% had a viral load of less than 50 copies/mL, and 50% had a viral load of less than 200 copies/mL.³⁶

Fostemsavir is the prodrug of temsavir, a first-in-class HIV-1 attachment inhibitor. It is used in patients with HIV disease who lack treatment options because of multidrug resistance or intolerance to other drugs. It is an oral drug to be taken twice a day. Fostemsavir was studied in 371 heavily treatment-experienced patients with multidrug-resistant HIV infection across 23 countries, with 272 patients undergoing treatment in the main randomized cohort (BRIGHTE trial). Patients in the main cohort received either fostemsavir or placebo twice daily for 8 days, in addition to their failing ART regimen. The remaining 99 patients received fostemsavir in a second nonrandomized cohort. Patients in the second cohort who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1. At week 48, 54% of the randomized group and 38% of the nonrandomized group achieved undetectable HIV viral loads (HIV RNA level < 40 copies/mL).³⁷

Pregnancy

ART is used during pregnancy to maintain the pregnant woman’s health and to prevent perinatal transmission. Pregnancy can present unique challenges to effective ART, and therapy decisions should be made based on short-term and long-term safety data, pharmacokinetics, and tolerability. With few exceptions, women who are on a stable ART regimen and present for care should continue the same regimen.³⁸ Key exceptions, due to increased toxicity, include didanosine, indinavir, nelfinavir, stavudine, and treatment-dose ritonavir. Cobicistat-based regimens (atazanavir, darunavir, elvitegravir) have altered pharmacokinetics during the second and third trimesters of pregnancy, leading to reduced mean steady-state minimum concentrations.³⁹ Because increasing plasma HIV RNA level is associated with transmission to infants, women continuing cobicistat-based ART treatments should undergo more frequent viral load measurements.⁴⁰ If viral rebound occurs late in pregnancy, especially shortly before delivery, achieving viral suppression can be more difficult. Therefore, women on a suppressed ART regimen containing cobicistat should consider switching to a different recommended regimen.³⁸

Both darunavir and atazanavir are considered preferred PI regimens in pregnancy. Darunavir’s median area under the concentration-time curve (AUC) is decreased by 38% and 39% in the second and third trimesters, respectively.⁴¹ During pregnancy, twice daily administration of darunavir/ritonavir 600 mg/100 mg is recommended. The pharmacokinetics of using twice-daily 800-mg darunavir is not supported and therefore not recommended.⁴² Similarly, the atazanavir AUC was 30% lower during the third trimester when atazanavir/ritonavir was used with TDF.⁴³ The package insert recommends using an increased dose of atazanavir/ritonavir (400 mg/100 mg) during pregnancy when used concomitantly with TDF or an H2-receptor blocker. Heartburn during pregnancy is common, and H2 blockers and proton pump inhibitors are considered safe during pregnancy, but are associated with drug-drug interactions.

Of the alternative regimens, rilpivirine-based regimens show highly variable pharmacokinetics during pregnancy, with AUC and trough concentrations between 20% and 50% lower.⁴⁴ While there is not sufficient data to recommend a change in dosing, women on rilpivirine-based regimens should have closer monitoring of HIV viral loads. Preliminary data from the Tsepamo Study, a birth surveillance study, suggested there is a higher risk of neural tube defects in children of women receiving dolutegravir. This led the World Health Organization and US Department of Health and Human Services to avoid using dolutegravir. Further follow-up showed that, although the risk is slightly higher, the difference is an additional 2 neural tube defects for every 1000 women exposed to the drug. However, dolutegravir offers great benefits, and thus the latest panel guidelines recommend use of dolutegravir as a preferred ART drug.⁴⁵

Geriatric Populations

Although HIV is seen predominantly in younger patients, 48% of persons living with HIV are older than 50 years and 8% are 65 years of age or older.⁴⁶ With effective antiretroviral treatment, we will continue to see an aging population of people living with HIV. There are no specific guidelines regarding the treatment of older adults, but HIV treatment can have its own challenges. Physiologic declines in renal function occur with aging, which can be compounded by an increasing prevalence of diabetes and decreased muscle mass, making estimations of renal function unreliable.⁴⁷ Physiologic changes with age, such as decline in renal and hepatic function, decreasing metabolism via cytochrome P450, and body composition, influence drug pharmacokinetics and can in turn potentiate drug toxicities.⁴⁸ Comorbid states and polypharmacy can complicate care. The prevalence of polypharmacy in the elderly is high, 93%, and is increasing.^49,50 A study found that in those aged 65 years or older with HIV, 65% had at least 1 potential drug-drug interaction, and 6.6% had a potential severe drug-drug interaction.⁵⁰ These patients are thus at risk of poor drug adherence, which in HIV therapy can lead to rebound viremia and resistance.

Optimizing ART in older adults also needs to account for greater comorbidities. For individuals at risk of osteopenia or osteoporosis, expert guidance suggests a benefit from regimens that spare the use of TDF or boosted PIs.⁵¹ Similarly, exposure to TDF and atazanavir has been suggested as potentially nephrotoxic, and avoiding these regimens in older patients should be considered.⁵²

Renal Insufficiency

Several commonly used ART agents have nephrotoxic potential. The most common manifestations of nephrotoxicity are tubular toxicity, crystal nephropathy, and interstitial nephritis. Of these, acute tubular toxicity caused by TDF is the most widely reported. About 2% of those taking TDF developed treatment-limiting renal insufficiency, manifested as Fanconi syndrome.⁵³ Higher plasma levels of TDF are associated with increased nephrotoxicity.⁵⁵ Guidelines recommend switching from TDF if the estimated glomerular filtration rate (eGFR) declines by > 25% or the eGFr is < 60/mL/min/1.73 m². Wever et al reports that in TDF-associated nephrotoxicity, only 42% of patients reached their pre-TDF eGFR.⁵⁴TAF, a prodrug of TDF, is associated with reduced levels of TDF and is hypothesized to have fewer adverse effects.⁵⁵ A pooled analysis comparing renal adverse effects of TDF and TAF reported no cases of renal dysfunction in the TAF group, supporting its safety; however, acute kidney injury has also been reported with TAF.^56,57 Switching from TDF to TAF in patients with renal dysfunction has been shown to lead to improvement in proteinuria, but the impact remains unclear.⁵³

Rarely, crystal nephropathy and interstitial nephritis are associated with indinavir and atazanavir therapy, which can progress to glomerulonephritis if not recognized.⁵⁹ Transitioning to another PI or INSTI is an appropriate strategy. It should be noted that dolutegravir, raltegravir, and the pharmacokinetic enhancer cobicistat increase serum creatinine up to 0.2 mg/dL via altered proximal tubular secretion of creatinine, but do not affect the actual GFR, and thus no medication adjustment is necessary.⁶⁰ If kidney injury is secondary to intrinsic nephrotoxic effects of ART, switching ART may be required.

Dyslipidemia and Cardiovascular Risk

Aside from the traditional cardiovascular risks, PIs, TAF, and efavirenz can negatively affect the lipid profile, with changes in LDL and triglycerides appearing as early as 2 weeks after initiating therapy. An observational study from Spain showed that treatment with TAF worsens the lipid profile in comparison to patients treated with TDF for elvitegravir/cobicistat-based therapies; patients on TAF were twice as likely to need lipid-lower drugs in comparison to those in the TDF arm.⁶¹ Similarly, patients who changed from a TDF-based regimen to TAF for improved renal and bone safety profiles had significant changes in both total cholesterol and LDL.⁶⁵Other NRTIs do not negatively affect lipid profile. Although NNRTIs can increase LDL, this is usually offset by an increase in HDL.⁶² Of the NNRTIs, the incidence of increased LDL is higher with efavirenz, but it also can cause an increase in HDL; in contrast, patients switched from efavirenz to rilpivirine have a better lipid profile.^63,64 PIs, especially older ones such as lopinavir/ritonavir, are associated with lipid abnormalities. For patients who develop dyslipidemia as a result of using older PIs, switching to a darunavir or atazanavir regimen or even integrase inhibitors, which are considered lipid neutral, is recommended.⁶³ When making adjustments in ART, care should be taken in prescribing abacavir to individuals with risk factors for coronary artery disease. Although there is no consensus, some randomized controlled trials suggested an association between myocardial infarction and abacavir, whereas others have not.^66,67

Because cardiovascular disease is a leading cause of death among people living with HIV, clinicians should remain mindful of the risks posed by some antiretroviral agents and consider use of lipid-neutral agents and modification of risk factors.

HIV and Hepatis B Co-infection

In patients with HIV and hepatitis B co-infection, ART regimens should contain 1 drug that is active against hepatitis B (lamivudine, emtricitabine, TDF, or TAF). Clinicians should monitor liver function for hepatitis B reactivation and liver function when a regimen that contains anti-hepatitis B drugs is stopped because discontinuation of these regimens can result in acute, and sometimes fatal, liver damage.²

Financial Considerations

With out-of-pocket expenses and co-pays, some patients may have to switch ART regimens for financial reasons. Additionally, switching to generic versions of ART has been proposed as a means of saving resources for government programs already facing budgetary constraints. A study published in 2013 using generic-based ART versus branded ART showed a potential savings of almost $1 billion per year.⁶⁸ A key barrier to the use of generic-based ART is patient skepticism regarding the performance of these medications. Branded ART regimens are also co-formulated, creating the perception that taking more pills will lead to noncompliance and therefore place the patient at risk of viral rebound. In a study from France, only 17% of patients were willing to switch to generic medications if doing so increased pill burden.⁶⁹ In the same study, 75% physicians were generally willing to prescribe generics; however, that number dropped to 26% if the patient’s pill burden would increase.⁶⁹ Paradoxically, because of the patchwork of insurance, government assistance, Medicaid, and Medicare, changing to generic-based ART may increase patients’ co-pays.

A 57-year-old man living with HIV has been followed at a local infectious disease clinic for more than 15 years. He acquired HIV disease through heterosexual contact. He lives alone and works at a convenience store; he has not been sexually active for the past 5 years. He smokes 10 cigarettes a day, but does not drink alcohol or use illicit drugs. He had been on coformulated emtricitabine/tenofovir disoproxil fumarate (TDF) and coformulated lopinavir/ritonavir, which he had taken conscientiously, since May 2008, without noticing any adverse reactions from this regimen. His HIV viral load had been undetectable, and his CD4 count had hovered between 600 and 700 cells/µL. Although he was on atorvastatin for dyslipidemia, his fasting lipid profile, performed in 2018, revealed a total cholesterol level of 200 mg/dL;triglyceride, 247 mg/dL; high-density lipoprotein (HDL), 43 mg/dL; and low-density lipoprotein (LDL), 132 mg/dL. In April 2019, his HIV regimen was switched to bictegravir/emtricitabine/tenofovir alafenamide (TAF). Blood tests performed in December 2019 revealed undetectable HIV viral load; an increased CD4 count to 849 cell/µL; total cholesterol, 140 mg/dL; triglyceride, 115 mg/dL; HDL, 60 mg/dL; and LDL, 90 mg/dL.

In this case, the cliché “if it’s not broke, don’t fix it” might not hold true. This patient continued to do well, with relatively high CD4 counts and undetectable HIV viral load on the same regimen for 11 years. However, after his ART regimen was switched, his CD4 count increased further, and there was a significant improvement in his lipid profile. Smoking, HIV disease, and suboptimal lipid profile are 3 cardiovascular risk factors for this patient; the lipid profile improved by just switching the ART regimen.

In this article, we discuss simplifying and switching ART in treatment-experienced patients living with HIV across various scenarios. Currently, the International AIDS Society-USA recommends treating all patients living with HIV, regardless of CD4 count.¹ Treatment decisions should be individualized by assessing patient readiness. Other factors that must be addressed when considering simplifying or switching an ART regimen in patients whose HIV disease is well controlled virologically and who do not have drug-resistance issues are listed in Table 1.

SIMPLIFYING ART

Virologically Suppressed Patients Without Drug-Resistant Virus

Treatment adherence is of paramount importance to ensure treatment success. Patients with a viral load that is undetectable or nearly undetectable without drug resistance could be taking ART regimens consisting of more than 1 pill and/or that require more than once-daily dosing. Decreasing pill burden or dosing frequency can help to improve adherence to treatment. In addition, older-generation ART agents are usually more toxic and less potent than newer-generation agents, so another important objective of switching older drugs to newer drugs is to decrease adverse reactions and improve virologic suppression. Selection of an ART regimen should be guided by the results of resistance testing (genotyping and phenotyping tests) and previous treatment history. After switching a patient’s ART regimen, plasma HIV viral load and CD4 count should be closely monitored.² The following 3-drug, single-tablet, once-daily ART regimens can be used in patients who are virologically stable (ordered chronologically by FDA approval dates).

Efavirenz/Emtricitabine/TDF (Atripla)

Coformulated efavirenz/emtricitabine/TDF was the first single-tablet, once-daily, fixed-dose combination approved by the FDA (July 2006). Approval was based on a 48- week clinical trial involving 244 adults with HIV infection that showed that 80% of participants achieved a marked reduction in HIV viral load and a significant increase in CD4 cell count.³ Of the 3 components, efavirenz has unique central nervous system (CNS) adverse effects that could reduce adherence. Patients who were started on this fixed-dose combination commonly reported dizziness, headache, nightmare, insomnia, and impaired concentration.⁴ However, the CNS side effects resolved within the first 4 weeks of therapy, and less than 5% of patients quit taking the drug. Primate studies showed efavirenz is teratogenic, but studies in pregnant women did not find efavirenz to be more teratogenic than other ART agents.⁵

The generic version of Atripla, Symfi, is a coformulation of efavirenz/lamivudine/TDF that is considered interchangeable with Atripla. As noted, efavirenz-based ART regimens are well known for causing CNS side effects; however, the ENCORE-1 trial demonstrated that fewer side effects are noted when the standard dose of efavirenz, 600 mg, is lowered to 400 mg.⁶ Symfi Lo is an efavirenz/lamivudine/TDF single-tablet regimen that contains 400 mg of efavirenz.

Emtricitabine/Rilpivirine/TDF (Complera)

Coformulated emtricitabine/rilpivirine/TDF was approved based on data from two 48-week, phase 3, double-blind, randomized controlled trials (ECHO and THRIVE) that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naive adults with HIV infection.^7,8 Rilpivirine is well tolerated and causes fewer CNS symptoms compared to efavirenz. The main caveat for rilpivirine is drug-drug interactions. It should not be coadministered with CYP inducers, such as rifampin, phenytoin, or St. John’s wort, as coadministration can cause subtherapeutic blood levels of rilpivirine. Because increased levels of rilpivirine can prolong QTc on electrocardiogram (ECG), an ECG should be obtained before starting an ART regimen that contains rilpivirine, especially in the presence of CYP 3A4 inhibitors.⁹

Elvitegravir/Cobicistat/Emtricitabine/TDF (Stribild)

This coformulation was approved based on data from 2 randomized, double-blind, controlled trials, Study 102 and Study 103, in treatment-naive patients with HIV (n = 1408). In Study 102, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or efavirenz/emtricitabine/TDF (Atripla).¹⁰ In Study 103, participants were randomized to receive either elvitegravir/cobicistat/emtricitabine/TDF or atazanavir + ritonavir + emtricitabine/TDF. In both studies, the primary endpoint was virologic success (HIV-1 RNA < 50 copies/mL) at 48 weeks, and elvitegravir/cobicistat/emtricitabine/TDF was noninferior compared to the other regimens.¹¹

Cobicistat is needed to boost elvitegravir to therapeutic blood levels. Cobicistat is a ritonavir analogue, but has no antiretroviral activity per se. It is used exclusively as a pharmacokinetic enhancer because it is a potent CYP 3A4 inhibitor. Because cobicistat can boost the blood level of many drugs other than elvitegravir, a thorough review of the patient’s medications list should be conducted before prescribing an ART regimen that contains cobicistat to prevent serious drug-drug interactions. Because cobicistat can block transport of creatinine in the proximal tubular, a small increase in serum creatinine can be seen in some patients.¹²

Abacavir/Dolutegravir/Lamivudine (Triumeq)

Approval of abacavir/dolutegravir/lamivudine (Triumeq) in August 2014 was based on SINGLE, a noninferiority trial involving 833 treatment-naive adults that compared dolutegravir and abacavir/lamivudine (the separate components of Triumeq) to efavirenz/emtricitabine/TDF. At 96 weeks, more patients in the dolutegravir and abacavir/lamivudine arm achieved an undetectable HIV viral load (80% versus 72%).¹³

Abacavir can cause a potentially fatal hypersensitivity syndrome in susceptible patients. The syndrome is characterized by fever, malaise, maculopapular rash, and gastrointestinal complaints (eg, nausea, vomiting, anorexia, abdominal pain and diarrhea). When abacavir-induced hypersensitivity syndrome is suspected, the drug should be stopped immediately and must never be restarted. The hypersensitivity syndrome is an immune response linked to the HLA-B*5701 allele, and patients should be tested for this genetic variation before starting an ART regimen that contains abacavir.¹⁴

Elvitegravir/Cobicistat/Emtricitabine/TAF (Genvoya)

Approval of coformulated elvitegravir/cobicistat/emtricitabine/TAF was supported by data from two 48-week phase 3, double-blind studies (Studies 104 and 111) involving 1733 treatment-naive patients that compared the regimen to elvitegravir/cobicistat/emtricitabine/TDF (Stribild). Both studies demonstrated that elvitegravir/cobicistat/emtricitabine/TAF was statistically noninferior, and it was favored in regard to certain renal and bone laboratory parameters.¹⁵ Studies comparing TAF and TDF have demonstrated that TAF is less likely to cause loss of bone mineral density and nephrotoxicity compared to TDF.^16,17

Emtricitabine/Rilpivirine/TAF (Odefsey)

Coformulated emtricitabine/rilpivirine/TAF was approved based, in part, on positive bioequivalence studies demonstrating that it achieved similar drug levels of emtricitabine and TAF as coformulated elvitegravir/cobicistat/emtricitabine/TAF and similar drug levels of rilpivirine as individually dosed rilpivirine.¹⁸ The safety, efficacy, and tolerability of this coformulation is supported by clinical studies of rilpivirine-based therapy and emtricitabine/TAF-based therapy in a range of patients with HIV.¹⁸

Bictegravir/Emtricitabine/TAF (Biktarvy)

The coformulation bictegravir/emtricitabine/TAF was approved based on 4 phase 3 studies: Studies 1489 and 1490 in treatment-naive adults, and Studies 1844 and 1878 in virologically suppressed adults. In Study 1489, 629 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or coformulated abacavir/dolutegravir/lamivudine. At week 48, similar percentages of patients in each arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL. In Study 1490, 645 treatment-naive adults were randomized 1:1 to receive coformulated bictegravir/emtricitabine/TAF or dolutegravir + emtricitabine/TAF. At week 48, similar percentages of patients in each arm achieved the primary endpoint of virologic success (HIV-1 RNA < 50 copies/mL).^19,20

Bictegravir is used in Biktarvy in place of the elvitegravir/cobicistat combination used in Genvoya. This non-cobicistat regimen has the advantage of having a lower risk of serious drug-drug interactions.

Darunavir/Cobicistat/Emtricitabine/TAF (Symtuza)

Approval of coformulated darunavir/cobicistat/emtricitabine/TAF was based on data from two 48-week, noninferiority, phase 3 studies that assessed the safety and efficacy of the coformulation versus a control regimen (darunavir/cobicistat plus emtricitabine/TDF) in adults with no prior ART history (AMBER) and in virologically suppressed adults (EMERALD). In the randomized, double-blind, multicenter controlled AMBER trial, at week 48, 91.4% of patients in the study group and 88.4% in the control group achieved viral suppression (HIV-1 RNA < 50 copies/mL), and virologic failure rates were low in both groups (HIV-1 RNA ≥ 50 copies/mL; 4.4% versus 3.3%, respectively).²¹

The randomized, double-blind, multicenter controlled EMERALD trial compared coformulated darunavir/cobicistat/emtricitabine/TAF to continuing a boosted PI plus emtricitabine and TDF in virologically suppressed patients who were already on a boosted PI–based regimen. At week 48, 2.5% of patients on coformulated darunavir/cobicistat/emtricitabine/TAF versus 2.1% on the control regimen had rebound HIV-1 RNA ≥ 50 copies/mL, and high virologic suppression rates were observed in both groups (HIV-1 RNA < 50 copies/mL: 94.9% versus 93.7%, respectively).²²

Doravirine/Lamivudine/TDF (Delstrigo)

Coformulated doravirine/lamivudine/TDF was approved based on data from 2 randomized, double-blind, controlled phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD. The former trial compared coformulated doravirine/lamivudine/TDF with efavirenz/emtricitabine/TDF in 728 treatment-naive patients. At 48 weeks, 84.3% in the doravirine/lamivudine/TDF arm and 80.8% in the efavirenz/emtricitabine/TDF arm met the primary endpoint of HIV-1 RNA < 50 copies/mL. Thus, doravirine/lamivudine/TDF showed sustained viral suppression and noninferiority compared to efavirenz/emtricitabine/TDF.²³ The DRIVE-FORWARD trial investigated doravirine compared with ritonavir-boosted darunavir, each in combination with 2 NRTIs (TDF with emtricitabine or abacavir with lamivudine). At week 48, 84% of patients in the doravirine arm and 80% in the ritonavir-boosted darunavir arm achieved the primary endpoint of HIV-1 RNA < 50 copies/mL.²⁴

Two-Drug, Single-Tablet, Once-Daily Regimens

Experts have long recommended that optimal treatment of HIV must consist of 3 active drugs, with trials both in the United States and Europe demonstrating decreased morbidity and mortality with 3-drug therapy.^25,26 However, newer, more potent 2-drug therapy is giving more choices to people living with HIV. The single-tablet, 2-drug regimens currently available are dolutegravir/rilpivirine and dolutegravir/lamivudine. There are theoretical benefits of 2-drug therapy, such as minimizing long-term toxicities, avoidance of some drug-drug interactions, and preservation of drugs for future treatment options. At this time, a 2-drug simplification regimen can be a viable option for selected virologically stable populations.

Dolutegravir/Rilpivirine (Juluca)

Dolutegravir/rilpivirine has been shown to be noninferior to standard therapy at 48-weeks, although it is associated with a higher discontinuation rate because of side effects.²⁷ This option can be particularly useful in patients who have contraindications to NRTIs or renal dysfunction, but it has been studied only in patients without resistance who are already virologically suppressed. Ongoing studies are looking at 2-versus 3-drug therapies for HIV treatment-experienced patients. Most of these use PIs as a backbone because of their potency and high barrier to resistance. The advent of second-generation integrase inhibitors offers additional options.

Dolutegravir/Lamivudine (Dovato)

The GEMINI-1 and GEMINI-2 trials demonstrated that dolutegravir/lamivudine was noninferior to dolutegravir/TDF/emtricitabine.²⁸ Based on these 2 studies, new guidelines have added dolutegravir/lamivudine as a recommended first-line therapy. For now, the recommendation is to use dolutegravir/lamivudine in individuals where NRTIs are contraindicated, and it should not be used in patients with chronic hepatitis B. Additionally, 3 studies have demonstrated the safety and efficacy of switching to dolutegravir/lamivudine.^29-31 In the TANGO trial, neither virologic failures nor resistant virus were identified at 48 weeks following the switch.³² Although there are benefits of simplification with this regimen, including lower toxicity, lower costs, and saving other NRTIs in case of resistance, there should be no rush to switch patients to a 2-drug regimen. This is a viable strategy in patients without baseline resistance who have preserved T-cells and do not have hepatitis B.

SWITCHING ART AGENTS IN SELECTED CLINICAL SCENARIOS

Virologic Failure

One of the main goals of ART is maximal and durable suppression of HIV viral load to prevent the development of drug-resistant mutations.² When patients are unable to achieve durable virologic suppression or have virologic rebound, the cause of virologic failure needs to be investigated. Virologic failure is defined as the inability to achieve or maintain viral suppression to a level below 200 copies/mL, whereas rebound is defined as an HIV RNA level exceeding 200 copies/mL after virologic suppression.³³ A common cause of virologic failure is patient nonadherence, which can be related to a range of factors, including psychosocial issues and affordability of medications. Innate viral resistance can be the result of transmitted drug resistance at the time of infection or be acquired during unsuppressed viral replication secondary to inherent error-prone reverse transcriptase.³³ Pharmacokinetic factors that affect blood levels of ART, such as drug-drug interactions, also can be a key factor in HIV drug resistance.

Clinical decisions regarding patients with virologic failure are based on baseline viral load and results from genotypic resistance assays. These assays are routinely done to identify mutations associated with drug resistance. Standard resistance testing is carried out when the viral load exceeds 1000 copies/mL, but it should be attempted when the viral load is greater than 500 copies/mL.² Furthermore, testing should be done while the patient is on ART or within 4 weeks of discontinuing treatment. Although a genotype assay may be done more than 4 weeks after stopping therapy, detectability of major mutations declines rapidly.³⁴ Stanford University offers an online public database of HIV drug resistance data (https://hivdb.stanford.edu/pages/genotype-rx.html).

Those who have a baseline viral load greater than the lower limit of detection, but consistently less than 200 copies/mL, are considered at low risk for subsequent development of viral resistance, and therefore do not routinely require a change in ART.³⁵ When viral loads are between 200 and 1000 copies/mL, efforts should be made to obtain a genotype, especially if the viral load exceeds 500 copies/mL; management of these patients is the same as management for those with a viral load exceeding 1000 copies/mL. When the viral load is too low to obtain a resistance assay, empiric changes to ART should be done on a case-by-case basis.² In these cases, if no empiric changes are made, repeat viral load testing is recommended and genotype testing can be performed once the viral load exceeds 500 copies/mL.

Management of patients with a viral load exceeding 1000 copies/mL is guided by the results of genotype testing. If resistance is not found, then ongoing counseling for adherence and/or determining whether there are drug-drug or drug-food interactions causing suboptimal drug levels are recommended. For patients with drug-resistant virus, current guidelines recommend that the new regimen should contain at least2, preferably 3, fully active drugs; moreover, these drugs should be based on drug resistance characteristics and, ideally, different mechanisms of action.² Any change should also take into account other medical conditions, such as hepatitis B, coronary artery disease, chronic kidney disease, and pregnancy status.

The goal of changing ART should be re-suppression, whenever possible. Designing a new regimen following failure of the primary regimen is based on the general principles listed in Table 2.

Patients With Limited Treatment Options

Despite advances in ART, some patients exhaust the existing regimens, leading to development of multidrug resistance and limited treatment options. In light of the treatment challenges in this group of patients, the FDA has recently approved 2 antiretroviral agents to target multidrug-resistant HIV: ibalizumab and fostemsavir.

Ibalizumab is a humanized IgG4 monoclonal antibody that blocks the entry of HIV through noncompetitive binding to the primary receptor of CD4 cells. It is used for the treatment of HIV infection in heavily treatment-
experienced patients with multidrug-resistant advanced HIV infection who are failing their current ART regimen. Ibalizumab is administered intravenously once a week.

Ibalizumab was studied in a multicenter, open-label, phase 3 trial that enrolled 40 adults in whom multiple ART regimens failed because of multidrug-resistant HIV infection. All the patients had a viral load of more than 1000 copies/mL. Patients received a loading dose of 2000 mg of ibalizumab with their current failing regimen for 1 week, and then received 800 mg of ibalizumab every 14 days, combined with an optimized treatment regimen for 6 months. After 1 week of ibalizumab therapy, 83% of the patients experienced a decrease in viral load. After 6 months, 43% had a viral load of less than 50 copies/mL, and 50% had a viral load of less than 200 copies/mL.³⁶

Fostemsavir is the prodrug of temsavir, a first-in-class HIV-1 attachment inhibitor. It is used in patients with HIV disease who lack treatment options because of multidrug resistance or intolerance to other drugs. It is an oral drug to be taken twice a day. Fostemsavir was studied in 371 heavily treatment-experienced patients with multidrug-resistant HIV infection across 23 countries, with 272 patients undergoing treatment in the main randomized cohort (BRIGHTE trial). Patients in the main cohort received either fostemsavir or placebo twice daily for 8 days, in addition to their failing ART regimen. The remaining 99 patients received fostemsavir in a second nonrandomized cohort. Patients in the second cohort who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1. At week 48, 54% of the randomized group and 38% of the nonrandomized group achieved undetectable HIV viral loads (HIV RNA level < 40 copies/mL).³⁷

Pregnancy

ART is used during pregnancy to maintain the pregnant woman’s health and to prevent perinatal transmission. Pregnancy can present unique challenges to effective ART, and therapy decisions should be made based on short-term and long-term safety data, pharmacokinetics, and tolerability. With few exceptions, women who are on a stable ART regimen and present for care should continue the same regimen.³⁸ Key exceptions, due to increased toxicity, include didanosine, indinavir, nelfinavir, stavudine, and treatment-dose ritonavir. Cobicistat-based regimens (atazanavir, darunavir, elvitegravir) have altered pharmacokinetics during the second and third trimesters of pregnancy, leading to reduced mean steady-state minimum concentrations.³⁹ Because increasing plasma HIV RNA level is associated with transmission to infants, women continuing cobicistat-based ART treatments should undergo more frequent viral load measurements.⁴⁰ If viral rebound occurs late in pregnancy, especially shortly before delivery, achieving viral suppression can be more difficult. Therefore, women on a suppressed ART regimen containing cobicistat should consider switching to a different recommended regimen.³⁸

Both darunavir and atazanavir are considered preferred PI regimens in pregnancy. Darunavir’s median area under the concentration-time curve (AUC) is decreased by 38% and 39% in the second and third trimesters, respectively.⁴¹ During pregnancy, twice daily administration of darunavir/ritonavir 600 mg/100 mg is recommended. The pharmacokinetics of using twice-daily 800-mg darunavir is not supported and therefore not recommended.⁴² Similarly, the atazanavir AUC was 30% lower during the third trimester when atazanavir/ritonavir was used with TDF.⁴³ The package insert recommends using an increased dose of atazanavir/ritonavir (400 mg/100 mg) during pregnancy when used concomitantly with TDF or an H2-receptor blocker. Heartburn during pregnancy is common, and H2 blockers and proton pump inhibitors are considered safe during pregnancy, but are associated with drug-drug interactions.

Of the alternative regimens, rilpivirine-based regimens show highly variable pharmacokinetics during pregnancy, with AUC and trough concentrations between 20% and 50% lower.⁴⁴ While there is not sufficient data to recommend a change in dosing, women on rilpivirine-based regimens should have closer monitoring of HIV viral loads. Preliminary data from the Tsepamo Study, a birth surveillance study, suggested there is a higher risk of neural tube defects in children of women receiving dolutegravir. This led the World Health Organization and US Department of Health and Human Services to avoid using dolutegravir. Further follow-up showed that, although the risk is slightly higher, the difference is an additional 2 neural tube defects for every 1000 women exposed to the drug. However, dolutegravir offers great benefits, and thus the latest panel guidelines recommend use of dolutegravir as a preferred ART drug.⁴⁵

Geriatric Populations

Although HIV is seen predominantly in younger patients, 48% of persons living with HIV are older than 50 years and 8% are 65 years of age or older.⁴⁶ With effective antiretroviral treatment, we will continue to see an aging population of people living with HIV. There are no specific guidelines regarding the treatment of older adults, but HIV treatment can have its own challenges. Physiologic declines in renal function occur with aging, which can be compounded by an increasing prevalence of diabetes and decreased muscle mass, making estimations of renal function unreliable.⁴⁷ Physiologic changes with age, such as decline in renal and hepatic function, decreasing metabolism via cytochrome P450, and body composition, influence drug pharmacokinetics and can in turn potentiate drug toxicities.⁴⁸ Comorbid states and polypharmacy can complicate care. The prevalence of polypharmacy in the elderly is high, 93%, and is increasing.^49,50 A study found that in those aged 65 years or older with HIV, 65% had at least 1 potential drug-drug interaction, and 6.6% had a potential severe drug-drug interaction.⁵⁰ These patients are thus at risk of poor drug adherence, which in HIV therapy can lead to rebound viremia and resistance.

Optimizing ART in older adults also needs to account for greater comorbidities. For individuals at risk of osteopenia or osteoporosis, expert guidance suggests a benefit from regimens that spare the use of TDF or boosted PIs.⁵¹ Similarly, exposure to TDF and atazanavir has been suggested as potentially nephrotoxic, and avoiding these regimens in older patients should be considered.⁵²

Renal Insufficiency

Several commonly used ART agents have nephrotoxic potential. The most common manifestations of nephrotoxicity are tubular toxicity, crystal nephropathy, and interstitial nephritis. Of these, acute tubular toxicity caused by TDF is the most widely reported. About 2% of those taking TDF developed treatment-limiting renal insufficiency, manifested as Fanconi syndrome.⁵³ Higher plasma levels of TDF are associated with increased nephrotoxicity.⁵⁵ Guidelines recommend switching from TDF if the estimated glomerular filtration rate (eGFR) declines by > 25% or the eGFr is < 60/mL/min/1.73 m². Wever et al reports that in TDF-associated nephrotoxicity, only 42% of patients reached their pre-TDF eGFR.⁵⁴TAF, a prodrug of TDF, is associated with reduced levels of TDF and is hypothesized to have fewer adverse effects.⁵⁵ A pooled analysis comparing renal adverse effects of TDF and TAF reported no cases of renal dysfunction in the TAF group, supporting its safety; however, acute kidney injury has also been reported with TAF.^56,57 Switching from TDF to TAF in patients with renal dysfunction has been shown to lead to improvement in proteinuria, but the impact remains unclear.⁵³

Rarely, crystal nephropathy and interstitial nephritis are associated with indinavir and atazanavir therapy, which can progress to glomerulonephritis if not recognized.⁵⁹ Transitioning to another PI or INSTI is an appropriate strategy. It should be noted that dolutegravir, raltegravir, and the pharmacokinetic enhancer cobicistat increase serum creatinine up to 0.2 mg/dL via altered proximal tubular secretion of creatinine, but do not affect the actual GFR, and thus no medication adjustment is necessary.⁶⁰ If kidney injury is secondary to intrinsic nephrotoxic effects of ART, switching ART may be required.

Dyslipidemia and Cardiovascular Risk

Aside from the traditional cardiovascular risks, PIs, TAF, and efavirenz can negatively affect the lipid profile, with changes in LDL and triglycerides appearing as early as 2 weeks after initiating therapy. An observational study from Spain showed that treatment with TAF worsens the lipid profile in comparison to patients treated with TDF for elvitegravir/cobicistat-based therapies; patients on TAF were twice as likely to need lipid-lower drugs in comparison to those in the TDF arm.⁶¹ Similarly, patients who changed from a TDF-based regimen to TAF for improved renal and bone safety profiles had significant changes in both total cholesterol and LDL.⁶⁵Other NRTIs do not negatively affect lipid profile. Although NNRTIs can increase LDL, this is usually offset by an increase in HDL.⁶² Of the NNRTIs, the incidence of increased LDL is higher with efavirenz, but it also can cause an increase in HDL; in contrast, patients switched from efavirenz to rilpivirine have a better lipid profile.^63,64 PIs, especially older ones such as lopinavir/ritonavir, are associated with lipid abnormalities. For patients who develop dyslipidemia as a result of using older PIs, switching to a darunavir or atazanavir regimen or even integrase inhibitors, which are considered lipid neutral, is recommended.⁶³ When making adjustments in ART, care should be taken in prescribing abacavir to individuals with risk factors for coronary artery disease. Although there is no consensus, some randomized controlled trials suggested an association between myocardial infarction and abacavir, whereas others have not.^66,67

Because cardiovascular disease is a leading cause of death among people living with HIV, clinicians should remain mindful of the risks posed by some antiretroviral agents and consider use of lipid-neutral agents and modification of risk factors.

HIV and Hepatis B Co-infection

In patients with HIV and hepatitis B co-infection, ART regimens should contain 1 drug that is active against hepatitis B (lamivudine, emtricitabine, TDF, or TAF). Clinicians should monitor liver function for hepatitis B reactivation and liver function when a regimen that contains anti-hepatitis B drugs is stopped because discontinuation of these regimens can result in acute, and sometimes fatal, liver damage.²

Financial Considerations

With out-of-pocket expenses and co-pays, some patients may have to switch ART regimens for financial reasons. Additionally, switching to generic versions of ART has been proposed as a means of saving resources for government programs already facing budgetary constraints. A study published in 2013 using generic-based ART versus branded ART showed a potential savings of almost $1 billion per year.⁶⁸ A key barrier to the use of generic-based ART is patient skepticism regarding the performance of these medications. Branded ART regimens are also co-formulated, creating the perception that taking more pills will lead to noncompliance and therefore place the patient at risk of viral rebound. In a study from France, only 17% of patients were willing to switch to generic medications if doing so increased pill burden.⁶⁹ In the same study, 75% physicians were generally willing to prescribe generics; however, that number dropped to 26% if the patient’s pill burden would increase.⁶⁹ Paradoxically, because of the patchwork of insurance, government assistance, Medicaid, and Medicare, changing to generic-based ART may increase patients’ co-pays.