Liz Scherer

The future of preexposure prophylaxis (PrEP) is here, according to interim study results demonstrating the superiority of long-acting, injectable cabotegravir (CAB-LA) over the current workhorse, daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC).

In a prospective, phase 2b-3 randomized, double-blind, double-dummy, active-controlled trial among 4,566 cisgender MSM (men who have sex with men) and transgender women, CAB-LA was shown to reduce risk for HIV infection by 66%. The study was terminated early, owing to strong evidence of efficacy in the first preplanned interim endpoint analysis. The study findings were published Aug. 11 in the New England Journal of Medicine.

“The lesson is not that TDF-FTC doesn’t work or has major problems; it is a very safe, very well-tolerated agent and astonishingly effective if taken as prescribed,” Raphael J. Landovitz, MD, lead author and codirector of the Center for HIV Identification, Prevention, and Treatment Services at the University of California, Los Angeles, said in an interview.

“The reason that we were able to show that cabotegravir was superior is because we enrolled a very young, very highly at-risk, very underresourced, underrepresented, highly sexually active group who weren’t able to take PrEP the way it was prescribed,” he said.

Study participants were assigned to receive either active CAB 600 mg intramuscularly with TDF-FTC placebo or active TDF-FTC (300 mg/200 mg) with a CAB procedure in three phases:
 

• An oral-tablet 5-week lead-in phase, a blinded injection phase beginning at week 5.
• An injection at week 9 and every 8 weeks thereafter through week 153.
• An open-label “tail” phase consisting of oral TDF/FTC to provide ongoing for participants discontinuing injections.

The median age of study participants was 26 years (interquartile range [IQR], 22-32 years); 12.5% (570) identified as transgender women; 49.8% (845/1,698) of U.S. participants were Black patients.

During follow-up, HIV infections were identified in 57 participants, including 52 who acquired HIV infections after enrollment (13 in the CAB group, incidence 0.41 per 100 person-years, vs. 39 in the TDF-FTC group, incidence 1.22 per 100 person-years). The hazard ratio for incident HIV infection was 0.34 (95% confidence interval, 0.18-0.62) CAB vs. TDF-FTC (P < .001). Consistent effects were observed across prespecified subgroups and populations.

Among participants in the CAB group, integrase strand-transfer inhibitor resistance mutations were detected in one of four of the baseline HIV infection cases. Among participants in the TDF-FTC group, 2 of 39 incident infections occurred despite drug concentration measurements that indicated good PrEP adherence.

Although injection site reactions were reported in 81.4% (1,724) of the CAB group, only 2.4% of patients (50) discontinued treatment. Most reactions began a median of 1 day (IQR, 0-2 days) post injection. They were of mild to moderate severity (60.8% pain, 23.7% tenderness) and lasted a median of 3 days (IQR, 2-6 days). Injection site reactions were reported in 31.3% of the participants in the TDF-FTC group who received at least one placebo injection.

Rates of severe adverse effects (grade 3 or higher) were similar between participants in the CAB and TDF-FTC groups. They consisted mostly of an increase in creatine kinase level (14.2% with CAB vs. 13.5% with TDF-FTC) and a decrease in creatine clearance (7.0% with CAB vs. 8.3% with TDF-FTC).

In a post hoc analysis, the mean annualized weight increase was 1.23 kg/y (95% CI, 1.05-1.42) in the CAB group, compared with 0.37 kg/y (95% CI, 0.18-0.55) in the TDF-FTC group. Most of these differences were observed during the first 40 weeks and were driven by weight loss among TDF-FTC participants; weight changes between groups were similar thereafter (~1 kg/y for both groups).
 

New modality, new challenges

“We’re constantly searching for new modalities to expand our repertoire of what we can provide patients, especially those folks with the highest need for PrEP,” Lina Rosengren-Hovee, MD, assistant professor of medicine and infectious disease specialist at UNC-Health, Chapel Hill, N.C., said in an interview. “Being able to offer an injectable option is going to be a game changer, but it will be critical to pinpoint structural factors that affect adherence,” she added.

Dr. Rosengren-Hovee also pointed to cases of integrase inhibitor resistance (both in the study and the larger clinical arena), which she believes are concerning. “It’s still a conversation that you’ll want to have with a patient; I wonder if we need more discussion about how we handle that in the clinical setting, even if it’s fairly uncommon,” she said.

When asked, Dr. Landovitz emphasized the rarity of breakthrough cases but acknowledged that there appears to be a pattern whereby the first breakthrough occurs with a trickle of virus and then bursts out with higher levels of virus at some point.

“CDC is actually thinking very hard about whether these long-acting PrEP agents obligate a change to the HIV screening process [e.g., a viral load or RNA-based test] rather than a conventional HIV test,” Dr. Landovitz said. He went on to say that in the ongoing, open-label portion of the study, investigators hope to learn whether one can avoid resistance by catching the first breakthrough earlier. That would help inform clinical implementation, he explained. He said that he challenges practitioners and health care communities to avoid some of the mistakes made with the oral PrEP rollout, namely, universal access without proper implementation of planning and testing protocols.

“By default, PrEP is much more decentralized and demedicalized, especially in primary care,” said Dr. Rosengren-Hovee. “We need more studies looking at real-world scenarios.”

Dr. Rosengren-Hovee reports no relevant financial relationships. Dr. Landovitz has consulting relationships with Gilead, Janssen, Roche, and Cepheus.

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

The future of preexposure prophylaxis (PrEP) is here, according to interim study results demonstrating the superiority of long-acting, injectable cabotegravir (CAB-LA) over the current workhorse, daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC).

In a prospective, phase 2b-3 randomized, double-blind, double-dummy, active-controlled trial among 4,566 cisgender MSM (men who have sex with men) and transgender women, CAB-LA was shown to reduce risk for HIV infection by 66%. The study was terminated early, owing to strong evidence of efficacy in the first preplanned interim endpoint analysis. The study findings were published Aug. 11 in the New England Journal of Medicine.

“The lesson is not that TDF-FTC doesn’t work or has major problems; it is a very safe, very well-tolerated agent and astonishingly effective if taken as prescribed,” Raphael J. Landovitz, MD, lead author and codirector of the Center for HIV Identification, Prevention, and Treatment Services at the University of California, Los Angeles, said in an interview.

“The reason that we were able to show that cabotegravir was superior is because we enrolled a very young, very highly at-risk, very underresourced, underrepresented, highly sexually active group who weren’t able to take PrEP the way it was prescribed,” he said.

Study participants were assigned to receive either active CAB 600 mg intramuscularly with TDF-FTC placebo or active TDF-FTC (300 mg/200 mg) with a CAB procedure in three phases:
 

• An oral-tablet 5-week lead-in phase, a blinded injection phase beginning at week 5.
• An injection at week 9 and every 8 weeks thereafter through week 153.
• An open-label “tail” phase consisting of oral TDF/FTC to provide ongoing for participants discontinuing injections.

The median age of study participants was 26 years (interquartile range [IQR], 22-32 years); 12.5% (570) identified as transgender women; 49.8% (845/1,698) of U.S. participants were Black patients.

During follow-up, HIV infections were identified in 57 participants, including 52 who acquired HIV infections after enrollment (13 in the CAB group, incidence 0.41 per 100 person-years, vs. 39 in the TDF-FTC group, incidence 1.22 per 100 person-years). The hazard ratio for incident HIV infection was 0.34 (95% confidence interval, 0.18-0.62) CAB vs. TDF-FTC (P < .001). Consistent effects were observed across prespecified subgroups and populations.

Among participants in the CAB group, integrase strand-transfer inhibitor resistance mutations were detected in one of four of the baseline HIV infection cases. Among participants in the TDF-FTC group, 2 of 39 incident infections occurred despite drug concentration measurements that indicated good PrEP adherence.

Although injection site reactions were reported in 81.4% (1,724) of the CAB group, only 2.4% of patients (50) discontinued treatment. Most reactions began a median of 1 day (IQR, 0-2 days) post injection. They were of mild to moderate severity (60.8% pain, 23.7% tenderness) and lasted a median of 3 days (IQR, 2-6 days). Injection site reactions were reported in 31.3% of the participants in the TDF-FTC group who received at least one placebo injection.

Rates of severe adverse effects (grade 3 or higher) were similar between participants in the CAB and TDF-FTC groups. They consisted mostly of an increase in creatine kinase level (14.2% with CAB vs. 13.5% with TDF-FTC) and a decrease in creatine clearance (7.0% with CAB vs. 8.3% with TDF-FTC).

In a post hoc analysis, the mean annualized weight increase was 1.23 kg/y (95% CI, 1.05-1.42) in the CAB group, compared with 0.37 kg/y (95% CI, 0.18-0.55) in the TDF-FTC group. Most of these differences were observed during the first 40 weeks and were driven by weight loss among TDF-FTC participants; weight changes between groups were similar thereafter (~1 kg/y for both groups).
 

New modality, new challenges

“We’re constantly searching for new modalities to expand our repertoire of what we can provide patients, especially those folks with the highest need for PrEP,” Lina Rosengren-Hovee, MD, assistant professor of medicine and infectious disease specialist at UNC-Health, Chapel Hill, N.C., said in an interview. “Being able to offer an injectable option is going to be a game changer, but it will be critical to pinpoint structural factors that affect adherence,” she added.

Dr. Rosengren-Hovee also pointed to cases of integrase inhibitor resistance (both in the study and the larger clinical arena), which she believes are concerning. “It’s still a conversation that you’ll want to have with a patient; I wonder if we need more discussion about how we handle that in the clinical setting, even if it’s fairly uncommon,” she said.

When asked, Dr. Landovitz emphasized the rarity of breakthrough cases but acknowledged that there appears to be a pattern whereby the first breakthrough occurs with a trickle of virus and then bursts out with higher levels of virus at some point.

“CDC is actually thinking very hard about whether these long-acting PrEP agents obligate a change to the HIV screening process [e.g., a viral load or RNA-based test] rather than a conventional HIV test,” Dr. Landovitz said. He went on to say that in the ongoing, open-label portion of the study, investigators hope to learn whether one can avoid resistance by catching the first breakthrough earlier. That would help inform clinical implementation, he explained. He said that he challenges practitioners and health care communities to avoid some of the mistakes made with the oral PrEP rollout, namely, universal access without proper implementation of planning and testing protocols.

“By default, PrEP is much more decentralized and demedicalized, especially in primary care,” said Dr. Rosengren-Hovee. “We need more studies looking at real-world scenarios.”

Dr. Rosengren-Hovee reports no relevant financial relationships. Dr. Landovitz has consulting relationships with Gilead, Janssen, Roche, and Cepheus.

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

The future of preexposure prophylaxis (PrEP) is here, according to interim study results demonstrating the superiority of long-acting, injectable cabotegravir (CAB-LA) over the current workhorse, daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC).

In a prospective, phase 2b-3 randomized, double-blind, double-dummy, active-controlled trial among 4,566 cisgender MSM (men who have sex with men) and transgender women, CAB-LA was shown to reduce risk for HIV infection by 66%. The study was terminated early, owing to strong evidence of efficacy in the first preplanned interim endpoint analysis. The study findings were published Aug. 11 in the New England Journal of Medicine.

“The lesson is not that TDF-FTC doesn’t work or has major problems; it is a very safe, very well-tolerated agent and astonishingly effective if taken as prescribed,” Raphael J. Landovitz, MD, lead author and codirector of the Center for HIV Identification, Prevention, and Treatment Services at the University of California, Los Angeles, said in an interview.

“The reason that we were able to show that cabotegravir was superior is because we enrolled a very young, very highly at-risk, very underresourced, underrepresented, highly sexually active group who weren’t able to take PrEP the way it was prescribed,” he said.

Study participants were assigned to receive either active CAB 600 mg intramuscularly with TDF-FTC placebo or active TDF-FTC (300 mg/200 mg) with a CAB procedure in three phases:
 

• An oral-tablet 5-week lead-in phase, a blinded injection phase beginning at week 5.
• An injection at week 9 and every 8 weeks thereafter through week 153.
• An open-label “tail” phase consisting of oral TDF/FTC to provide ongoing for participants discontinuing injections.

The median age of study participants was 26 years (interquartile range [IQR], 22-32 years); 12.5% (570) identified as transgender women; 49.8% (845/1,698) of U.S. participants were Black patients.

During follow-up, HIV infections were identified in 57 participants, including 52 who acquired HIV infections after enrollment (13 in the CAB group, incidence 0.41 per 100 person-years, vs. 39 in the TDF-FTC group, incidence 1.22 per 100 person-years). The hazard ratio for incident HIV infection was 0.34 (95% confidence interval, 0.18-0.62) CAB vs. TDF-FTC (P < .001). Consistent effects were observed across prespecified subgroups and populations.

Among participants in the CAB group, integrase strand-transfer inhibitor resistance mutations were detected in one of four of the baseline HIV infection cases. Among participants in the TDF-FTC group, 2 of 39 incident infections occurred despite drug concentration measurements that indicated good PrEP adherence.

Although injection site reactions were reported in 81.4% (1,724) of the CAB group, only 2.4% of patients (50) discontinued treatment. Most reactions began a median of 1 day (IQR, 0-2 days) post injection. They were of mild to moderate severity (60.8% pain, 23.7% tenderness) and lasted a median of 3 days (IQR, 2-6 days). Injection site reactions were reported in 31.3% of the participants in the TDF-FTC group who received at least one placebo injection.

Rates of severe adverse effects (grade 3 or higher) were similar between participants in the CAB and TDF-FTC groups. They consisted mostly of an increase in creatine kinase level (14.2% with CAB vs. 13.5% with TDF-FTC) and a decrease in creatine clearance (7.0% with CAB vs. 8.3% with TDF-FTC).

In a post hoc analysis, the mean annualized weight increase was 1.23 kg/y (95% CI, 1.05-1.42) in the CAB group, compared with 0.37 kg/y (95% CI, 0.18-0.55) in the TDF-FTC group. Most of these differences were observed during the first 40 weeks and were driven by weight loss among TDF-FTC participants; weight changes between groups were similar thereafter (~1 kg/y for both groups).
 

New modality, new challenges

“We’re constantly searching for new modalities to expand our repertoire of what we can provide patients, especially those folks with the highest need for PrEP,” Lina Rosengren-Hovee, MD, assistant professor of medicine and infectious disease specialist at UNC-Health, Chapel Hill, N.C., said in an interview. “Being able to offer an injectable option is going to be a game changer, but it will be critical to pinpoint structural factors that affect adherence,” she added.

Dr. Rosengren-Hovee also pointed to cases of integrase inhibitor resistance (both in the study and the larger clinical arena), which she believes are concerning. “It’s still a conversation that you’ll want to have with a patient; I wonder if we need more discussion about how we handle that in the clinical setting, even if it’s fairly uncommon,” she said.

When asked, Dr. Landovitz emphasized the rarity of breakthrough cases but acknowledged that there appears to be a pattern whereby the first breakthrough occurs with a trickle of virus and then bursts out with higher levels of virus at some point.

“CDC is actually thinking very hard about whether these long-acting PrEP agents obligate a change to the HIV screening process [e.g., a viral load or RNA-based test] rather than a conventional HIV test,” Dr. Landovitz said. He went on to say that in the ongoing, open-label portion of the study, investigators hope to learn whether one can avoid resistance by catching the first breakthrough earlier. That would help inform clinical implementation, he explained. He said that he challenges practitioners and health care communities to avoid some of the mistakes made with the oral PrEP rollout, namely, universal access without proper implementation of planning and testing protocols.

“By default, PrEP is much more decentralized and demedicalized, especially in primary care,” said Dr. Rosengren-Hovee. “We need more studies looking at real-world scenarios.”

Dr. Rosengren-Hovee reports no relevant financial relationships. Dr. Landovitz has consulting relationships with Gilead, Janssen, Roche, and Cepheus.

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

“One of the most important considerations before switching HIV patients to injectable long-acting cabotegravir/rilpivirine [CAB/RPV LA; Cabenuva, ViiV Healthcare] is for the patient and the clinician to arrive at this decision together,” Elliot DeHaan, MD, told this news organization. “This therapy is not necessarily for everyone.”

Dr. DeHaan is lead author of the newly released clinical guideline from the New York State Department of Health AIDS Institute for use of CAB/RPV LA as replacement antiretroviral therapy (ART) in virally suppressed adults with HIV. He explained that the guidance expands upon Health & Human Services’ Feb. 24 CAB/RPV LA recommendations, highlighting some of the most important clinical and patient considerations necessary to implement injectable ART. “There are a lot of things that need to be laid out beforehand,” he said.
 

Gaining consensus

Approved by the FDA in late January 2021, CAB/RPV LA is considered an optimization strategy for individuals with HIV whose virus is suppressed by oral ART and who might prefer monthly injections to daily oral therapy. While there are various reasons why patients might wish to switch to a long-acting injectable, one of the primary concerns is adherence. Of note, the guidance points to phase 3 clinical study findings that suggest high levels (86%-91%) of patient satisfaction with CAB/RPV LA, which portends a promising future for this therapeutic approach.

With regard to patient preference, recommendations focus on the need to thoroughly discuss several critical requisites with potential candidates, including a 4-week lead-in daily oral ART course (CAB [Vocabria] 30 mg, RPV [Edurant] 25 mg) before initiating a loading dose. Patients should be advised of the potential for development of resistance should dosing be interrupted for any reason (CAB and RPV have extended half-lives ranging from mean 5.6 to 11.5 weeks for CAB and 13 to 28 weeks for RPV), as well as the need to return to oral bridging therapy if subsequent injections are not administered within the 7-day window period. If the maintenance dose is delayed beyond 2 months, a loading dose and restart is necessary.

CAB/RPV LA therapy is administered into opposing gluteal muscles (CAB into one gluteus medius and RPV into the contralateral gluteus medius), and injection-site pain beginning 1 day post-injection and lasting 3-4 days is common. In phase 3 clinical trials, as many as 83% of patients experienced adverse effects (AEs), which also include nodules, induration, and swelling at the injection sites. Fortunately, 99% of AEs were of mild to moderate severity. While pain tends to decline over several injections, Dr. DeHaan said that it’s an important part of the initial discussion about switching therapies.
 

Other considerations

Prior resistance testing, ART treatment history, and/or baseline genotypic resistance testing that includes both reverse transcriptase and integrase genes should be reviewed or conducted before initiating treatment. K103 mutations alone are not considered exclusionary. Virologic failures (defined as two consecutive plasma HIV-1 RNA measurements greater than 200 copies/mL), while rare, were reported in 13 clinical trial participants. Recent data suggest that patients who developed resistance despite adherence had at least two of three factors: a body mass index greater than 30 kg/m², the HIV-1 subtype A6/A1, and the presence of proviral RPV RAMS.

CAB/RPV LA does not treat hepatitis B (HBV) coinfections, reinforcing the need for concurrent oral HBV therapy.

And there’s a paucity of data on the safety and efficacy of CAB/RPV in children and adolescents, or during pregnancy/lactation, precluding its use in those patient populations.
 

Clinical, institutional considerations

Adaptation of CAB/RPV LA as ART requires specific clinical institutional planning, especially in light of current pandemic-related resource and staffing limitations. Monthly dosing must be done within a 7-day window and requires preparations akin to initial loading doses. In addition to pharmacy resources and onsite storage requirements, the guidance points to patient scheduling and reminder systems, access (patient transportation, work constraints, parking), and most importantly, contingency plans for care (including oral bridging therapy) should a clinic be forced to shut down for any reason. Additional factors include billing protocols, insurance or third party authorizations, and provision of counseling and education training.

“Given that this is a completely new way of thinking among providers, we’re all learning together,” said David Koren, PharmD, MPH, a clinical pharmacy specialist in infectious diseases at Temple University, Philadelphia. “The guidelines provide a nice framework for taking the next step to operationalize these processes into practice, taking into account that barriers to implementation are still unknown.” Dr. Koren was not involved in the development of the guidelines.

Dr. DeHaan has disclosed no relevant financial relationships. Dr. Koren disclosed serving on a prior Advisory Panel for ViiV Healthcare US.

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

“One of the most important considerations before switching HIV patients to injectable long-acting cabotegravir/rilpivirine [CAB/RPV LA; Cabenuva, ViiV Healthcare] is for the patient and the clinician to arrive at this decision together,” Elliot DeHaan, MD, told this news organization. “This therapy is not necessarily for everyone.”

Dr. DeHaan is lead author of the newly released clinical guideline from the New York State Department of Health AIDS Institute for use of CAB/RPV LA as replacement antiretroviral therapy (ART) in virally suppressed adults with HIV. He explained that the guidance expands upon Health & Human Services’ Feb. 24 CAB/RPV LA recommendations, highlighting some of the most important clinical and patient considerations necessary to implement injectable ART. “There are a lot of things that need to be laid out beforehand,” he said.
 

Gaining consensus

Approved by the FDA in late January 2021, CAB/RPV LA is considered an optimization strategy for individuals with HIV whose virus is suppressed by oral ART and who might prefer monthly injections to daily oral therapy. While there are various reasons why patients might wish to switch to a long-acting injectable, one of the primary concerns is adherence. Of note, the guidance points to phase 3 clinical study findings that suggest high levels (86%-91%) of patient satisfaction with CAB/RPV LA, which portends a promising future for this therapeutic approach.

With regard to patient preference, recommendations focus on the need to thoroughly discuss several critical requisites with potential candidates, including a 4-week lead-in daily oral ART course (CAB [Vocabria] 30 mg, RPV [Edurant] 25 mg) before initiating a loading dose. Patients should be advised of the potential for development of resistance should dosing be interrupted for any reason (CAB and RPV have extended half-lives ranging from mean 5.6 to 11.5 weeks for CAB and 13 to 28 weeks for RPV), as well as the need to return to oral bridging therapy if subsequent injections are not administered within the 7-day window period. If the maintenance dose is delayed beyond 2 months, a loading dose and restart is necessary.

CAB/RPV LA therapy is administered into opposing gluteal muscles (CAB into one gluteus medius and RPV into the contralateral gluteus medius), and injection-site pain beginning 1 day post-injection and lasting 3-4 days is common. In phase 3 clinical trials, as many as 83% of patients experienced adverse effects (AEs), which also include nodules, induration, and swelling at the injection sites. Fortunately, 99% of AEs were of mild to moderate severity. While pain tends to decline over several injections, Dr. DeHaan said that it’s an important part of the initial discussion about switching therapies.
 

Other considerations

Prior resistance testing, ART treatment history, and/or baseline genotypic resistance testing that includes both reverse transcriptase and integrase genes should be reviewed or conducted before initiating treatment. K103 mutations alone are not considered exclusionary. Virologic failures (defined as two consecutive plasma HIV-1 RNA measurements greater than 200 copies/mL), while rare, were reported in 13 clinical trial participants. Recent data suggest that patients who developed resistance despite adherence had at least two of three factors: a body mass index greater than 30 kg/m², the HIV-1 subtype A6/A1, and the presence of proviral RPV RAMS.

CAB/RPV LA does not treat hepatitis B (HBV) coinfections, reinforcing the need for concurrent oral HBV therapy.

And there’s a paucity of data on the safety and efficacy of CAB/RPV in children and adolescents, or during pregnancy/lactation, precluding its use in those patient populations.
 

Clinical, institutional considerations

Adaptation of CAB/RPV LA as ART requires specific clinical institutional planning, especially in light of current pandemic-related resource and staffing limitations. Monthly dosing must be done within a 7-day window and requires preparations akin to initial loading doses. In addition to pharmacy resources and onsite storage requirements, the guidance points to patient scheduling and reminder systems, access (patient transportation, work constraints, parking), and most importantly, contingency plans for care (including oral bridging therapy) should a clinic be forced to shut down for any reason. Additional factors include billing protocols, insurance or third party authorizations, and provision of counseling and education training.

“Given that this is a completely new way of thinking among providers, we’re all learning together,” said David Koren, PharmD, MPH, a clinical pharmacy specialist in infectious diseases at Temple University, Philadelphia. “The guidelines provide a nice framework for taking the next step to operationalize these processes into practice, taking into account that barriers to implementation are still unknown.” Dr. Koren was not involved in the development of the guidelines.

Dr. DeHaan has disclosed no relevant financial relationships. Dr. Koren disclosed serving on a prior Advisory Panel for ViiV Healthcare US.

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

“One of the most important considerations before switching HIV patients to injectable long-acting cabotegravir/rilpivirine [CAB/RPV LA; Cabenuva, ViiV Healthcare] is for the patient and the clinician to arrive at this decision together,” Elliot DeHaan, MD, told this news organization. “This therapy is not necessarily for everyone.”

Dr. DeHaan is lead author of the newly released clinical guideline from the New York State Department of Health AIDS Institute for use of CAB/RPV LA as replacement antiretroviral therapy (ART) in virally suppressed adults with HIV. He explained that the guidance expands upon Health & Human Services’ Feb. 24 CAB/RPV LA recommendations, highlighting some of the most important clinical and patient considerations necessary to implement injectable ART. “There are a lot of things that need to be laid out beforehand,” he said.
 

Gaining consensus

Approved by the FDA in late January 2021, CAB/RPV LA is considered an optimization strategy for individuals with HIV whose virus is suppressed by oral ART and who might prefer monthly injections to daily oral therapy. While there are various reasons why patients might wish to switch to a long-acting injectable, one of the primary concerns is adherence. Of note, the guidance points to phase 3 clinical study findings that suggest high levels (86%-91%) of patient satisfaction with CAB/RPV LA, which portends a promising future for this therapeutic approach.

With regard to patient preference, recommendations focus on the need to thoroughly discuss several critical requisites with potential candidates, including a 4-week lead-in daily oral ART course (CAB [Vocabria] 30 mg, RPV [Edurant] 25 mg) before initiating a loading dose. Patients should be advised of the potential for development of resistance should dosing be interrupted for any reason (CAB and RPV have extended half-lives ranging from mean 5.6 to 11.5 weeks for CAB and 13 to 28 weeks for RPV), as well as the need to return to oral bridging therapy if subsequent injections are not administered within the 7-day window period. If the maintenance dose is delayed beyond 2 months, a loading dose and restart is necessary.

CAB/RPV LA therapy is administered into opposing gluteal muscles (CAB into one gluteus medius and RPV into the contralateral gluteus medius), and injection-site pain beginning 1 day post-injection and lasting 3-4 days is common. In phase 3 clinical trials, as many as 83% of patients experienced adverse effects (AEs), which also include nodules, induration, and swelling at the injection sites. Fortunately, 99% of AEs were of mild to moderate severity. While pain tends to decline over several injections, Dr. DeHaan said that it’s an important part of the initial discussion about switching therapies.
 

Other considerations

Prior resistance testing, ART treatment history, and/or baseline genotypic resistance testing that includes both reverse transcriptase and integrase genes should be reviewed or conducted before initiating treatment. K103 mutations alone are not considered exclusionary. Virologic failures (defined as two consecutive plasma HIV-1 RNA measurements greater than 200 copies/mL), while rare, were reported in 13 clinical trial participants. Recent data suggest that patients who developed resistance despite adherence had at least two of three factors: a body mass index greater than 30 kg/m², the HIV-1 subtype A6/A1, and the presence of proviral RPV RAMS.

CAB/RPV LA does not treat hepatitis B (HBV) coinfections, reinforcing the need for concurrent oral HBV therapy.

And there’s a paucity of data on the safety and efficacy of CAB/RPV in children and adolescents, or during pregnancy/lactation, precluding its use in those patient populations.
 

Clinical, institutional considerations

Adaptation of CAB/RPV LA as ART requires specific clinical institutional planning, especially in light of current pandemic-related resource and staffing limitations. Monthly dosing must be done within a 7-day window and requires preparations akin to initial loading doses. In addition to pharmacy resources and onsite storage requirements, the guidance points to patient scheduling and reminder systems, access (patient transportation, work constraints, parking), and most importantly, contingency plans for care (including oral bridging therapy) should a clinic be forced to shut down for any reason. Additional factors include billing protocols, insurance or third party authorizations, and provision of counseling and education training.

“Given that this is a completely new way of thinking among providers, we’re all learning together,” said David Koren, PharmD, MPH, a clinical pharmacy specialist in infectious diseases at Temple University, Philadelphia. “The guidelines provide a nice framework for taking the next step to operationalize these processes into practice, taking into account that barriers to implementation are still unknown.” Dr. Koren was not involved in the development of the guidelines.

Dr. DeHaan has disclosed no relevant financial relationships. Dr. Koren disclosed serving on a prior Advisory Panel for ViiV Healthcare US.

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

For many people, being told that they are HIV positive is no longer a death sentence. But for Robert Suttle, a Black gay man and social justice educator, it is a life sentence.

Unexpectedly caught up in the HIV criminalization web at the age of 30, Mr. Suttle spent 6 months in a Louisiana state prison for a consensual sexual relationship with an adult partner. The crime? Not disclosing his HIV-positive status, a charge that Mr. Suttle says is untrue.

“I did disclose my status to my partner; however, I can’t really answer how they might have received it,” he said.

Today, at the age of 42, Mr. Suttle still carries the indelible stain of a conviction and of being a registered sex offender. “After their diagnosis, criminal charge, and/or conviction, many people think they’re done – either ‘I’ve gotten out of prison’ or ‘I’m still on probation’ – whatever the case may be,” he explained. “But we’re still living out these collateral consequences, be it with housing, moving to another state, or finding a job.”

The same is true for HIV-positive people who are charged and tried but manage to dodge prison for one reason or another. Monique Howell, a straight, 40-year-old former army soldier and single mother of five children, said that she was afraid to disclose her HIV status to a sexual partner but did advise him to wear a condom.* She points to her DD14 discharge papers (i.e., forms that verify that someone served in the military) that were issued when her military duty was rescinded following the dismissal of her court case.

“I was going to reenlist, but I got in trouble,” she said. She explained that although a DD14 separation helps to ensure that she can receive benefits and care, the papers were issued with a caveat stating “serious offense,” an indelible stain that, like Mr. Suttle’s, will follow her for the rest of her life.
 

Laws criminalize myths and misconceptions

HIV criminalization laws subject persons whose behaviors may expose others to HIV to felony or misdemeanor charges. Depending on the state, they can carry prison terms ranging from less than 10 years to life, according to the Centers for Disease Control and Prevention.

Originally enacted at the height of the AIDS epidemic in 1986, when fear was rampant and hundreds were dying, the laws were intended to reduce HIV transmission. But they’ve had unintended consequences: Amplifying stigmatization and discrimination and perpetuating HIV myths and misconceptions, including how HIV is transmitted.

Decades of scientific advances challenge the most basic reasoning behind laws (for example, that transmission is possible via biting or spitting or through a single sexual act, which studies have shown poses a risk as low as 0%-1.4%). In addition, few laws reflect one of the most important HIV research findings of the past decade: undetectable equals untransmittable, meaning that the virus cannot be sexually transmitted by people who are taking antiretroviral therapy and whose viral loads are undetectable.

In most of these cases, individuals who are positive for HIV are charged and punished for unintentional exposure, not deliberate intent to harm. Moreover, for the charge to stick, sexual partners don’t need to have acquired the virus or prove the transmission source if they do become HIV positive.

Ms. Howell noted that it was the Army that brought the charges against her, not her sexual partner at that time (who, incidentally, tested negative). He even testified on her behalf at the trial. “I’ll never forget it,” she said. “He said, ‘I don’t want anything to happen to Monique; even if you put her behind bars, she’s still HIV-positive and she’s still got those children. She told me to get a condom, and I chose not to.’ ”
 

Criminal vs. clinical fallout

In 2018, 20 scientists across the world issued a consensus statement underscoring the fact that HIV criminalization laws are based on fallacies and faulty science. The statement (which remains one of the most accessed in the Journal of the International AIDS Society) also points out that 33 countries (including the United States) use general criminal statutes such as attempted murder or reckless endangerment to lengthen sentences when people with HIV commit crimes.

When the laws were created, “many were the equivalent [to general criminal laws], because HIV was seen as a death sentence,” explained Chris Beyrer MD, MPH, professor of public health and human rights at Johns Hopkins Bloomberg School of Public Health, Baltimore. “So, failure to disclose your status, to wear a condom was seen as risking someone else’s life, which is no longer the case,” he added.

In fact, “from the perspective of the kinds of impact that these laws have had on transmission, or risk, or behavior, what you find is that they really have no public health benefit and they have real public harms,” said Dr. Beyrer.

Claire Farel, MD, assistant professor and medical director of the UNC Infectious Diseases Clinic at the University of North Carolina at Chapel Hill, concurs. “Because of the criminalization undercurrent, there are people who don’t get tested, meaning that they are at risk for worse health outcomes, such as cancer, vascular disease, and of course HIV-related poor outcomes, including progression to AIDS.”

Farel also points to the residual stigma associated with HIV. “Much of this is inextricable from that surrounding homophobia, especially among young men of color who have sex with men. It opens up a larger conversation that a lot of people don’t want to engage in,” she said.
 

Laws broaden existing disparities even further

The CDC released a study June 4 showing substantial declines in the overall incidence of HIV in the United States, with an important caveat: There’s been a worsening disparity in cases. Access to care and engagement with care remain poor among certain populations. For example, Black individuals accounted for 41% of new HIV infections in 2019, but they represent only 12% of the U.S. population; Hispanic/Latinx persons accounted for 29% of new infections, although they represent only 17% of the entire population.

The same is true for HIV criminalization: In 2020, more than 50% of defendants were people of color, according to U.S. case data collated by the HIV Justice Network.

Still, the momentum to change these antiquated laws is gaining speed. In May, the Illinois State Senate passed a bill repealing HIV criminalization, and this past March, Virginia’s Governor Ralph Northam signed a bill lowering HIV-related criminalization charges from a felony to a misdemeanor and changing the wording of its law to include both intent and transmission.** California, Colorado, Iowa, Michigan, Nevada, and North Carolina have also modernized or repealed their laws.
 

Ending the U.S. HIV epidemic: Patients first

Without true HIV criminalization reform, efforts to change the public and clinical mindset regarding HIV from its being a highly stigmatized disease to a preventable, treatable infection are likely to fall short. Dr. Beyrer emphasized that the onus lies with the scientific and activist communities working together. “I don’t know how you can end the epidemic if you are still stigmatizing the people who are actually acquiring these infections,” he said.

There are steps that patients can take while these forces push for change.

“As people first process their diagnosis, they need to learn as much about HIV and the science behind it as possible,” advised Mr. Suttle. He said that to protect oneself, it’s essential to learn about HIV criminalization and the laws in one’s state.

“Find someone you can trust, starting with your medical provider if possible, and if you have a significant other, bring that person to your appointments so they can see that you are in care and doing all that you can do to lower viral loads and protect others,” he added.

Ms. Howell said that although people should be in treatment and care, attitudes also need to change on the clinician side. “We’re just given these meds, told to take them, and are sent on our merry ways, but they don’t tell us how to live our lives properly; nobody grabs us and says, hey, these are the laws and you need to know this or that.”

When a person who is HIV positive does get caught up in the system, if possible, that person should consult an attorney who understands these laws. Mr. Suttle suggested reaching out to organizations in the movement to end HIV criminalization (e.g., the Sero Project, the Center for HIV Law and Policy, or the Positive Women’s Network) for further support, help with cases (including providing experts to testify), social services, and other resources. Mr. Suttle also encourages people who need help and direction to reach out to him directly at rsuttle2000@gmail.com.

Forty years ago, the CDC published its first report of an illness in five healthy gay men living in Los Angeles. The first cases in women were reported shortly thereafter. Over the years, there have been many scientific advances in prevention and treatment. But as Dr. Beyrer aptly noted in an editorial published January 2021 in The Lancet HIV, “time has not lessened the sting of the early decades of AIDS.”

“We should not have to be afraid of who we are because we are HIV positive,” said Ms. Howell.

Dr. Farel, Mr. Suttle, and Ms. Howell report no relevant financial relationships. Dr. Beyrer has a consulting agreement with Merck.
 

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

*Correction, 6/14/2021: An earlier version of this story misstated Ms. Howell's age. She is 40.

**Correction, 6/14/2021: An earlier version of this story misspelled Gov. Northam's name.

For many people, being told that they are HIV positive is no longer a death sentence. But for Robert Suttle, a Black gay man and social justice educator, it is a life sentence.

Unexpectedly caught up in the HIV criminalization web at the age of 30, Mr. Suttle spent 6 months in a Louisiana state prison for a consensual sexual relationship with an adult partner. The crime? Not disclosing his HIV-positive status, a charge that Mr. Suttle says is untrue.

“I did disclose my status to my partner; however, I can’t really answer how they might have received it,” he said.

Today, at the age of 42, Mr. Suttle still carries the indelible stain of a conviction and of being a registered sex offender. “After their diagnosis, criminal charge, and/or conviction, many people think they’re done – either ‘I’ve gotten out of prison’ or ‘I’m still on probation’ – whatever the case may be,” he explained. “But we’re still living out these collateral consequences, be it with housing, moving to another state, or finding a job.”

The same is true for HIV-positive people who are charged and tried but manage to dodge prison for one reason or another. Monique Howell, a straight, 40-year-old former army soldier and single mother of five children, said that she was afraid to disclose her HIV status to a sexual partner but did advise him to wear a condom.* She points to her DD14 discharge papers (i.e., forms that verify that someone served in the military) that were issued when her military duty was rescinded following the dismissal of her court case.

“I was going to reenlist, but I got in trouble,” she said. She explained that although a DD14 separation helps to ensure that she can receive benefits and care, the papers were issued with a caveat stating “serious offense,” an indelible stain that, like Mr. Suttle’s, will follow her for the rest of her life.
 

Laws criminalize myths and misconceptions

HIV criminalization laws subject persons whose behaviors may expose others to HIV to felony or misdemeanor charges. Depending on the state, they can carry prison terms ranging from less than 10 years to life, according to the Centers for Disease Control and Prevention.

Originally enacted at the height of the AIDS epidemic in 1986, when fear was rampant and hundreds were dying, the laws were intended to reduce HIV transmission. But they’ve had unintended consequences: Amplifying stigmatization and discrimination and perpetuating HIV myths and misconceptions, including how HIV is transmitted.

Decades of scientific advances challenge the most basic reasoning behind laws (for example, that transmission is possible via biting or spitting or through a single sexual act, which studies have shown poses a risk as low as 0%-1.4%). In addition, few laws reflect one of the most important HIV research findings of the past decade: undetectable equals untransmittable, meaning that the virus cannot be sexually transmitted by people who are taking antiretroviral therapy and whose viral loads are undetectable.

In most of these cases, individuals who are positive for HIV are charged and punished for unintentional exposure, not deliberate intent to harm. Moreover, for the charge to stick, sexual partners don’t need to have acquired the virus or prove the transmission source if they do become HIV positive.

Ms. Howell noted that it was the Army that brought the charges against her, not her sexual partner at that time (who, incidentally, tested negative). He even testified on her behalf at the trial. “I’ll never forget it,” she said. “He said, ‘I don’t want anything to happen to Monique; even if you put her behind bars, she’s still HIV-positive and she’s still got those children. She told me to get a condom, and I chose not to.’ ”
 

Criminal vs. clinical fallout

In 2018, 20 scientists across the world issued a consensus statement underscoring the fact that HIV criminalization laws are based on fallacies and faulty science. The statement (which remains one of the most accessed in the Journal of the International AIDS Society) also points out that 33 countries (including the United States) use general criminal statutes such as attempted murder or reckless endangerment to lengthen sentences when people with HIV commit crimes.

When the laws were created, “many were the equivalent [to general criminal laws], because HIV was seen as a death sentence,” explained Chris Beyrer MD, MPH, professor of public health and human rights at Johns Hopkins Bloomberg School of Public Health, Baltimore. “So, failure to disclose your status, to wear a condom was seen as risking someone else’s life, which is no longer the case,” he added.

In fact, “from the perspective of the kinds of impact that these laws have had on transmission, or risk, or behavior, what you find is that they really have no public health benefit and they have real public harms,” said Dr. Beyrer.

Claire Farel, MD, assistant professor and medical director of the UNC Infectious Diseases Clinic at the University of North Carolina at Chapel Hill, concurs. “Because of the criminalization undercurrent, there are people who don’t get tested, meaning that they are at risk for worse health outcomes, such as cancer, vascular disease, and of course HIV-related poor outcomes, including progression to AIDS.”

Farel also points to the residual stigma associated with HIV. “Much of this is inextricable from that surrounding homophobia, especially among young men of color who have sex with men. It opens up a larger conversation that a lot of people don’t want to engage in,” she said.
 

Laws broaden existing disparities even further

The CDC released a study June 4 showing substantial declines in the overall incidence of HIV in the United States, with an important caveat: There’s been a worsening disparity in cases. Access to care and engagement with care remain poor among certain populations. For example, Black individuals accounted for 41% of new HIV infections in 2019, but they represent only 12% of the U.S. population; Hispanic/Latinx persons accounted for 29% of new infections, although they represent only 17% of the entire population.

The same is true for HIV criminalization: In 2020, more than 50% of defendants were people of color, according to U.S. case data collated by the HIV Justice Network.

Still, the momentum to change these antiquated laws is gaining speed. In May, the Illinois State Senate passed a bill repealing HIV criminalization, and this past March, Virginia’s Governor Ralph Northam signed a bill lowering HIV-related criminalization charges from a felony to a misdemeanor and changing the wording of its law to include both intent and transmission.** California, Colorado, Iowa, Michigan, Nevada, and North Carolina have also modernized or repealed their laws.
 

Ending the U.S. HIV epidemic: Patients first

Without true HIV criminalization reform, efforts to change the public and clinical mindset regarding HIV from its being a highly stigmatized disease to a preventable, treatable infection are likely to fall short. Dr. Beyrer emphasized that the onus lies with the scientific and activist communities working together. “I don’t know how you can end the epidemic if you are still stigmatizing the people who are actually acquiring these infections,” he said.

There are steps that patients can take while these forces push for change.

“As people first process their diagnosis, they need to learn as much about HIV and the science behind it as possible,” advised Mr. Suttle. He said that to protect oneself, it’s essential to learn about HIV criminalization and the laws in one’s state.

“Find someone you can trust, starting with your medical provider if possible, and if you have a significant other, bring that person to your appointments so they can see that you are in care and doing all that you can do to lower viral loads and protect others,” he added.

Ms. Howell said that although people should be in treatment and care, attitudes also need to change on the clinician side. “We’re just given these meds, told to take them, and are sent on our merry ways, but they don’t tell us how to live our lives properly; nobody grabs us and says, hey, these are the laws and you need to know this or that.”

When a person who is HIV positive does get caught up in the system, if possible, that person should consult an attorney who understands these laws. Mr. Suttle suggested reaching out to organizations in the movement to end HIV criminalization (e.g., the Sero Project, the Center for HIV Law and Policy, or the Positive Women’s Network) for further support, help with cases (including providing experts to testify), social services, and other resources. Mr. Suttle also encourages people who need help and direction to reach out to him directly at rsuttle2000@gmail.com.

Forty years ago, the CDC published its first report of an illness in five healthy gay men living in Los Angeles. The first cases in women were reported shortly thereafter. Over the years, there have been many scientific advances in prevention and treatment. But as Dr. Beyrer aptly noted in an editorial published January 2021 in The Lancet HIV, “time has not lessened the sting of the early decades of AIDS.”

“We should not have to be afraid of who we are because we are HIV positive,” said Ms. Howell.

Dr. Farel, Mr. Suttle, and Ms. Howell report no relevant financial relationships. Dr. Beyrer has a consulting agreement with Merck.
 

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

*Correction, 6/14/2021: An earlier version of this story misstated Ms. Howell's age. She is 40.

**Correction, 6/14/2021: An earlier version of this story misspelled Gov. Northam's name.

For many people, being told that they are HIV positive is no longer a death sentence. But for Robert Suttle, a Black gay man and social justice educator, it is a life sentence.

Unexpectedly caught up in the HIV criminalization web at the age of 30, Mr. Suttle spent 6 months in a Louisiana state prison for a consensual sexual relationship with an adult partner. The crime? Not disclosing his HIV-positive status, a charge that Mr. Suttle says is untrue.

“I did disclose my status to my partner; however, I can’t really answer how they might have received it,” he said.

Today, at the age of 42, Mr. Suttle still carries the indelible stain of a conviction and of being a registered sex offender. “After their diagnosis, criminal charge, and/or conviction, many people think they’re done – either ‘I’ve gotten out of prison’ or ‘I’m still on probation’ – whatever the case may be,” he explained. “But we’re still living out these collateral consequences, be it with housing, moving to another state, or finding a job.”

The same is true for HIV-positive people who are charged and tried but manage to dodge prison for one reason or another. Monique Howell, a straight, 40-year-old former army soldier and single mother of five children, said that she was afraid to disclose her HIV status to a sexual partner but did advise him to wear a condom.* She points to her DD14 discharge papers (i.e., forms that verify that someone served in the military) that were issued when her military duty was rescinded following the dismissal of her court case.

“I was going to reenlist, but I got in trouble,” she said. She explained that although a DD14 separation helps to ensure that she can receive benefits and care, the papers were issued with a caveat stating “serious offense,” an indelible stain that, like Mr. Suttle’s, will follow her for the rest of her life.
 

Laws criminalize myths and misconceptions

HIV criminalization laws subject persons whose behaviors may expose others to HIV to felony or misdemeanor charges. Depending on the state, they can carry prison terms ranging from less than 10 years to life, according to the Centers for Disease Control and Prevention.

Originally enacted at the height of the AIDS epidemic in 1986, when fear was rampant and hundreds were dying, the laws were intended to reduce HIV transmission. But they’ve had unintended consequences: Amplifying stigmatization and discrimination and perpetuating HIV myths and misconceptions, including how HIV is transmitted.

Decades of scientific advances challenge the most basic reasoning behind laws (for example, that transmission is possible via biting or spitting or through a single sexual act, which studies have shown poses a risk as low as 0%-1.4%). In addition, few laws reflect one of the most important HIV research findings of the past decade: undetectable equals untransmittable, meaning that the virus cannot be sexually transmitted by people who are taking antiretroviral therapy and whose viral loads are undetectable.

In most of these cases, individuals who are positive for HIV are charged and punished for unintentional exposure, not deliberate intent to harm. Moreover, for the charge to stick, sexual partners don’t need to have acquired the virus or prove the transmission source if they do become HIV positive.

Ms. Howell noted that it was the Army that brought the charges against her, not her sexual partner at that time (who, incidentally, tested negative). He even testified on her behalf at the trial. “I’ll never forget it,” she said. “He said, ‘I don’t want anything to happen to Monique; even if you put her behind bars, she’s still HIV-positive and she’s still got those children. She told me to get a condom, and I chose not to.’ ”
 

Criminal vs. clinical fallout

In 2018, 20 scientists across the world issued a consensus statement underscoring the fact that HIV criminalization laws are based on fallacies and faulty science. The statement (which remains one of the most accessed in the Journal of the International AIDS Society) also points out that 33 countries (including the United States) use general criminal statutes such as attempted murder or reckless endangerment to lengthen sentences when people with HIV commit crimes.

When the laws were created, “many were the equivalent [to general criminal laws], because HIV was seen as a death sentence,” explained Chris Beyrer MD, MPH, professor of public health and human rights at Johns Hopkins Bloomberg School of Public Health, Baltimore. “So, failure to disclose your status, to wear a condom was seen as risking someone else’s life, which is no longer the case,” he added.

In fact, “from the perspective of the kinds of impact that these laws have had on transmission, or risk, or behavior, what you find is that they really have no public health benefit and they have real public harms,” said Dr. Beyrer.

Claire Farel, MD, assistant professor and medical director of the UNC Infectious Diseases Clinic at the University of North Carolina at Chapel Hill, concurs. “Because of the criminalization undercurrent, there are people who don’t get tested, meaning that they are at risk for worse health outcomes, such as cancer, vascular disease, and of course HIV-related poor outcomes, including progression to AIDS.”

Farel also points to the residual stigma associated with HIV. “Much of this is inextricable from that surrounding homophobia, especially among young men of color who have sex with men. It opens up a larger conversation that a lot of people don’t want to engage in,” she said.
 

Laws broaden existing disparities even further

The CDC released a study June 4 showing substantial declines in the overall incidence of HIV in the United States, with an important caveat: There’s been a worsening disparity in cases. Access to care and engagement with care remain poor among certain populations. For example, Black individuals accounted for 41% of new HIV infections in 2019, but they represent only 12% of the U.S. population; Hispanic/Latinx persons accounted for 29% of new infections, although they represent only 17% of the entire population.

The same is true for HIV criminalization: In 2020, more than 50% of defendants were people of color, according to U.S. case data collated by the HIV Justice Network.

Still, the momentum to change these antiquated laws is gaining speed. In May, the Illinois State Senate passed a bill repealing HIV criminalization, and this past March, Virginia’s Governor Ralph Northam signed a bill lowering HIV-related criminalization charges from a felony to a misdemeanor and changing the wording of its law to include both intent and transmission.** California, Colorado, Iowa, Michigan, Nevada, and North Carolina have also modernized or repealed their laws.
 

Ending the U.S. HIV epidemic: Patients first

Without true HIV criminalization reform, efforts to change the public and clinical mindset regarding HIV from its being a highly stigmatized disease to a preventable, treatable infection are likely to fall short. Dr. Beyrer emphasized that the onus lies with the scientific and activist communities working together. “I don’t know how you can end the epidemic if you are still stigmatizing the people who are actually acquiring these infections,” he said.

There are steps that patients can take while these forces push for change.

“As people first process their diagnosis, they need to learn as much about HIV and the science behind it as possible,” advised Mr. Suttle. He said that to protect oneself, it’s essential to learn about HIV criminalization and the laws in one’s state.

“Find someone you can trust, starting with your medical provider if possible, and if you have a significant other, bring that person to your appointments so they can see that you are in care and doing all that you can do to lower viral loads and protect others,” he added.

Ms. Howell said that although people should be in treatment and care, attitudes also need to change on the clinician side. “We’re just given these meds, told to take them, and are sent on our merry ways, but they don’t tell us how to live our lives properly; nobody grabs us and says, hey, these are the laws and you need to know this or that.”

When a person who is HIV positive does get caught up in the system, if possible, that person should consult an attorney who understands these laws. Mr. Suttle suggested reaching out to organizations in the movement to end HIV criminalization (e.g., the Sero Project, the Center for HIV Law and Policy, or the Positive Women’s Network) for further support, help with cases (including providing experts to testify), social services, and other resources. Mr. Suttle also encourages people who need help and direction to reach out to him directly at rsuttle2000@gmail.com.

Forty years ago, the CDC published its first report of an illness in five healthy gay men living in Los Angeles. The first cases in women were reported shortly thereafter. Over the years, there have been many scientific advances in prevention and treatment. But as Dr. Beyrer aptly noted in an editorial published January 2021 in The Lancet HIV, “time has not lessened the sting of the early decades of AIDS.”

“We should not have to be afraid of who we are because we are HIV positive,” said Ms. Howell.

Dr. Farel, Mr. Suttle, and Ms. Howell report no relevant financial relationships. Dr. Beyrer has a consulting agreement with Merck.
 

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

*Correction, 6/14/2021: An earlier version of this story misstated Ms. Howell's age. She is 40.

**Correction, 6/14/2021: An earlier version of this story misspelled Gov. Northam's name.

“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).

Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.

Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.

PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared. Data that have accumulated since the COVID-19 outbreak suggest that at least 1 in 3 people who are initially infected may be long-haulers.

A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.

“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
 

Neurologic detritus

Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.

“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.

Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.

Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.

Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
 

Debilitating, pervasive symptoms

Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.

Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.

In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.

Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).

Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.

In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).

“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
 

Proliferation of long-COVID clinics

A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.

Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.

On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.

Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.

The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.

“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
 

An uphill battle

Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”

Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.

He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”

The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.

Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.

The interviewees have disclosed no relevant financial relationships.

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

“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).

Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.

Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.

PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared. Data that have accumulated since the COVID-19 outbreak suggest that at least 1 in 3 people who are initially infected may be long-haulers.

A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.

“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
 

Neurologic detritus

Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.

“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.

Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.

Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.

Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
 

Debilitating, pervasive symptoms

Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.

Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.

In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.

Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).

Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.

In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).

“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
 

Proliferation of long-COVID clinics

A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.

Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.

On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.

Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.

The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.

“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
 

An uphill battle

Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”

Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.

He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”

The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.

Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.

The interviewees have disclosed no relevant financial relationships.

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

“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” said Greg Vanichkachorn, MD, MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).

Take a nap. Tough it out. Push through it. Dr. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.

Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.

PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared. Data that have accumulated since the COVID-19 outbreak suggest that at least 1 in 3 people who are initially infected may be long-haulers.

A total of 33.6% (95% confidence interval, 11.17-34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36-13.33) represented first-time diagnoses.

“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg chair of neurology at University of Miami, and past president of the American Academy of Neurology.
 

Neurologic detritus

Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms. “What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.

“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.

Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.

Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery. Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.

Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection. Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.
 

Debilitating, pervasive symptoms

Findings from an international survey of 3,762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40-49 years; 25.0% were aged 50-59 years). For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.

Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.

In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.

Reports of even more severe neurologic first-time diagnoses are emerging. Findings from the Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10-0.20), ischemic stroke (0.43%; 95% CI, 0.36-0.52), parkinsonism (0.07%; 95% CI, 0.05-0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51-2.89).

Dr. Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.

In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0-3 [median, 0]; cardiovagal, 0-3 [median, 0]; cardiovascular adrenergic, 0-4 [median, 0]).

“The pattern that’s emerging is consistent with deconditioning,” Dr. Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”
 

Proliferation of long-COVID clinics

A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. “These post-viral, autonomic neuropathies tend to be self-limiting, but we’re starting to see different levels of involvement,” Dr. Toledano explained. At present, causality and/or underlying mechanisms are unclear.

Speaking on behalf of the American Academy of Neurology, Dr. Sacco acknowledged the challenges that lie ahead. “Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.

On the flip side, he pointed to the lessons of the past year and how quickly health care systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.

Across the nation, numerous hospitals and health care systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.

The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that under-resourced populations can access needed care and assistance.

“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Dr. Toledano. During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges. Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.
 

An uphill battle

Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work. “The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Dr. Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”

Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Dr. Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.

He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression. “This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”

The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.

Despite the challenges, Dr. Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.

The interviewees have disclosed no relevant financial relationships.

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

Accelerated brain aging among HIV-infected adults might be caused in part by altered deep sleep patterns, new research suggests.

Using a measure known as the brain age index (BAI) – a machine-learning model that measures deviations in brain activity during sleep relative to healthy individuals – investigators identified 34 sleep electroencephalogram features that were significantly altered by HIV infection. The most notable of these was the decline in slow-wave activity during non-REM sleep, which has been previously associated with MRI markers of brain aging in healthy adults.

“One of the functions of slow-wave sleep appears to be its association with the glymphatic system, which clears [metabolic] waste products and supports memory consolidation,” study coauthor Brandon Westover, MD, PhD, associate professor of neurology at Massachusetts General Hospital/Harvard Medical School, Boston, said in an interview. “It’s also believed to be associated with an accelerated risk for dementia and other cognitive issues.”

Previous work conducted at Johns Hopkins and other institutions confirm Dr. Westerson’s hypothesis. Charlene Gamaldo, MD, medical director of Johns Hopkins Sleep Disorders Center in Baltimore, pointed to other study findings in patients with neurodegenerative disease that have shown a link between predominant habitual sleep positions and dementia, potentially driven by inefficient glymphatic transport. Dr. Gamaldo was not involved in the current study.
 

Threefold acceleration vs. healthy volunteers

“We’ve been grappling with whether people with HIV on ART experience accelerated aging or accentuated aging,” coauthor Shibani Mukerji, MD, PhD, associate director of the neuroinfectious diseases unit at Massachusetts General, said in an interview. “We have yet to have biomarkers to address this question, and most of the tools are limited to invasive or expensive diagnostics. “In general, sleep and its influence on health have been understudied in the HIV population.”

To address this question, the researchers retrospectively examined a Massachusetts General Hospital database of diagnostic sleep study participants from 2008 to 2018, identifying 3,155 healthy, HIV-negative control subjects and 43 HIV-positive participants. Thirty-four (79%) of the HIV-positive participants were men, 30 (70%) were White, and 38 (93%) were virally suppressed at the time of their sleep study. Four patients were taking efavirenz, 13 were taking an integrase strand transfer inhibitor, and all were adherent to antiretroviral therapy (ART) at the time of their sleep study.

None of the HIV-positive participants had a history of secondary brain infection or brain tumor, although one patient had recovered fully from a previous HIV-associated encephalitis.

The study findings, which were published online March 30, 2021, in Sleep, first showed that HIV-positive participants had an average BAI of 3.19 years (standard error of the mean,1.43 years), compared with the control participants, who had an average BAI of –0.16 (SEM, 0.18 years).

These findings held after adjustment for potential confounders (age, sex, race, tobacco use disorder, and alcohol use disorder), yielding a total effect of HIV on BAI of 3.35 years (P < .01).

“Despite being well controlled on ART, HIV-positive individuals who had participated in the sleep studies still had elevated brain age,” said Dr. Westover. “We didn’t have enough information to determine the pathways by which HIV increases the BAI, but chronic inflammation appears to be an important factor.”

The findings also demonstrated that comorbidities accounted for roughly a quarter of the effect of HIV on BAI. However, the lack of statistical significance (in part because of the limited sample size) precluded the ability to determine if treating or preventing them might influence the degree to which HIV affects BAI and, in turn, cognitive decline.
 

HIV, sleep EEG, and brain aging

To estimate the effect of HIV on specific EEG features, the investigators again evaluated the total effect, this time replacing BAI with individual sleep EEG as the primary outcome. Among the 34 EEG features significantly altered by HIV, none were observed in the wake state and three were altered in REM (each associated with reduced delta band power). The rest were distributed in non-REM sleep, most notably in the deepest phase, corresponding to relative reductions in delta wave power.

The study findings build on the investigators’ previous research, which demonstrated an association between greater mean BAI and dementia, psychotic disorders, and anxiety/mood disorders in HIV-negative subjects, all of which correlated to attenuated slow-wave sleep.

More research is needed to determine if BAI, as it relates to sleep EEG, can effectively track the risk for cognitive decline among HIV-positive people, and if certain confounders might attenuate or accelerate this risk.

“While our team has not specifically looked at BAI, the findings in this study seem perfectly in line with what we have found with our own research,” Dr. Gamaldo said in an interview. “Not only have we observed a robust association between minimal cognitive deficits and patients’ sleep complaints (despite being virally controlled), but also, the potential value of measuring the architectural sleep features by ambulatory EEG to identify HIV patients’ vulnerability to cognitive decline.”

“BAI is a physiologic, easily repeatable measurement that can be used to track if an intervention is having a good effect,” Dr. Westover said.

Dr. Mukerji concurred, adding that “having a tool that can be used in resource-challenged settings and also be incorporated into longitudinal studies in a patient population with substantial age-related comorbidities, like HIV, would be really helpful.”

Dr. Westover and Dr. Mukerji disclosed no relevant financial relationships. Dr. Gamaldo is a consultant for Jazz Pharmaceuticals, and has received author royalties from UpToDate and honoraria from Medscape CME for content contribution.

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

Accelerated brain aging among HIV-infected adults might be caused in part by altered deep sleep patterns, new research suggests.

Using a measure known as the brain age index (BAI) – a machine-learning model that measures deviations in brain activity during sleep relative to healthy individuals – investigators identified 34 sleep electroencephalogram features that were significantly altered by HIV infection. The most notable of these was the decline in slow-wave activity during non-REM sleep, which has been previously associated with MRI markers of brain aging in healthy adults.

“One of the functions of slow-wave sleep appears to be its association with the glymphatic system, which clears [metabolic] waste products and supports memory consolidation,” study coauthor Brandon Westover, MD, PhD, associate professor of neurology at Massachusetts General Hospital/Harvard Medical School, Boston, said in an interview. “It’s also believed to be associated with an accelerated risk for dementia and other cognitive issues.”

Previous work conducted at Johns Hopkins and other institutions confirm Dr. Westerson’s hypothesis. Charlene Gamaldo, MD, medical director of Johns Hopkins Sleep Disorders Center in Baltimore, pointed to other study findings in patients with neurodegenerative disease that have shown a link between predominant habitual sleep positions and dementia, potentially driven by inefficient glymphatic transport. Dr. Gamaldo was not involved in the current study.
 

Threefold acceleration vs. healthy volunteers

“We’ve been grappling with whether people with HIV on ART experience accelerated aging or accentuated aging,” coauthor Shibani Mukerji, MD, PhD, associate director of the neuroinfectious diseases unit at Massachusetts General, said in an interview. “We have yet to have biomarkers to address this question, and most of the tools are limited to invasive or expensive diagnostics. “In general, sleep and its influence on health have been understudied in the HIV population.”

To address this question, the researchers retrospectively examined a Massachusetts General Hospital database of diagnostic sleep study participants from 2008 to 2018, identifying 3,155 healthy, HIV-negative control subjects and 43 HIV-positive participants. Thirty-four (79%) of the HIV-positive participants were men, 30 (70%) were White, and 38 (93%) were virally suppressed at the time of their sleep study. Four patients were taking efavirenz, 13 were taking an integrase strand transfer inhibitor, and all were adherent to antiretroviral therapy (ART) at the time of their sleep study.

None of the HIV-positive participants had a history of secondary brain infection or brain tumor, although one patient had recovered fully from a previous HIV-associated encephalitis.

The study findings, which were published online March 30, 2021, in Sleep, first showed that HIV-positive participants had an average BAI of 3.19 years (standard error of the mean,1.43 years), compared with the control participants, who had an average BAI of –0.16 (SEM, 0.18 years).

These findings held after adjustment for potential confounders (age, sex, race, tobacco use disorder, and alcohol use disorder), yielding a total effect of HIV on BAI of 3.35 years (P < .01).

“Despite being well controlled on ART, HIV-positive individuals who had participated in the sleep studies still had elevated brain age,” said Dr. Westover. “We didn’t have enough information to determine the pathways by which HIV increases the BAI, but chronic inflammation appears to be an important factor.”

The findings also demonstrated that comorbidities accounted for roughly a quarter of the effect of HIV on BAI. However, the lack of statistical significance (in part because of the limited sample size) precluded the ability to determine if treating or preventing them might influence the degree to which HIV affects BAI and, in turn, cognitive decline.
 

HIV, sleep EEG, and brain aging

To estimate the effect of HIV on specific EEG features, the investigators again evaluated the total effect, this time replacing BAI with individual sleep EEG as the primary outcome. Among the 34 EEG features significantly altered by HIV, none were observed in the wake state and three were altered in REM (each associated with reduced delta band power). The rest were distributed in non-REM sleep, most notably in the deepest phase, corresponding to relative reductions in delta wave power.

The study findings build on the investigators’ previous research, which demonstrated an association between greater mean BAI and dementia, psychotic disorders, and anxiety/mood disorders in HIV-negative subjects, all of which correlated to attenuated slow-wave sleep.

More research is needed to determine if BAI, as it relates to sleep EEG, can effectively track the risk for cognitive decline among HIV-positive people, and if certain confounders might attenuate or accelerate this risk.

“While our team has not specifically looked at BAI, the findings in this study seem perfectly in line with what we have found with our own research,” Dr. Gamaldo said in an interview. “Not only have we observed a robust association between minimal cognitive deficits and patients’ sleep complaints (despite being virally controlled), but also, the potential value of measuring the architectural sleep features by ambulatory EEG to identify HIV patients’ vulnerability to cognitive decline.”

“BAI is a physiologic, easily repeatable measurement that can be used to track if an intervention is having a good effect,” Dr. Westover said.

Dr. Mukerji concurred, adding that “having a tool that can be used in resource-challenged settings and also be incorporated into longitudinal studies in a patient population with substantial age-related comorbidities, like HIV, would be really helpful.”

Dr. Westover and Dr. Mukerji disclosed no relevant financial relationships. Dr. Gamaldo is a consultant for Jazz Pharmaceuticals, and has received author royalties from UpToDate and honoraria from Medscape CME for content contribution.

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

Accelerated brain aging among HIV-infected adults might be caused in part by altered deep sleep patterns, new research suggests.

Using a measure known as the brain age index (BAI) – a machine-learning model that measures deviations in brain activity during sleep relative to healthy individuals – investigators identified 34 sleep electroencephalogram features that were significantly altered by HIV infection. The most notable of these was the decline in slow-wave activity during non-REM sleep, which has been previously associated with MRI markers of brain aging in healthy adults.

“One of the functions of slow-wave sleep appears to be its association with the glymphatic system, which clears [metabolic] waste products and supports memory consolidation,” study coauthor Brandon Westover, MD, PhD, associate professor of neurology at Massachusetts General Hospital/Harvard Medical School, Boston, said in an interview. “It’s also believed to be associated with an accelerated risk for dementia and other cognitive issues.”

Previous work conducted at Johns Hopkins and other institutions confirm Dr. Westerson’s hypothesis. Charlene Gamaldo, MD, medical director of Johns Hopkins Sleep Disorders Center in Baltimore, pointed to other study findings in patients with neurodegenerative disease that have shown a link between predominant habitual sleep positions and dementia, potentially driven by inefficient glymphatic transport. Dr. Gamaldo was not involved in the current study.
 

Threefold acceleration vs. healthy volunteers

“We’ve been grappling with whether people with HIV on ART experience accelerated aging or accentuated aging,” coauthor Shibani Mukerji, MD, PhD, associate director of the neuroinfectious diseases unit at Massachusetts General, said in an interview. “We have yet to have biomarkers to address this question, and most of the tools are limited to invasive or expensive diagnostics. “In general, sleep and its influence on health have been understudied in the HIV population.”

To address this question, the researchers retrospectively examined a Massachusetts General Hospital database of diagnostic sleep study participants from 2008 to 2018, identifying 3,155 healthy, HIV-negative control subjects and 43 HIV-positive participants. Thirty-four (79%) of the HIV-positive participants were men, 30 (70%) were White, and 38 (93%) were virally suppressed at the time of their sleep study. Four patients were taking efavirenz, 13 were taking an integrase strand transfer inhibitor, and all were adherent to antiretroviral therapy (ART) at the time of their sleep study.

None of the HIV-positive participants had a history of secondary brain infection or brain tumor, although one patient had recovered fully from a previous HIV-associated encephalitis.

The study findings, which were published online March 30, 2021, in Sleep, first showed that HIV-positive participants had an average BAI of 3.19 years (standard error of the mean,1.43 years), compared with the control participants, who had an average BAI of –0.16 (SEM, 0.18 years).

These findings held after adjustment for potential confounders (age, sex, race, tobacco use disorder, and alcohol use disorder), yielding a total effect of HIV on BAI of 3.35 years (P < .01).

“Despite being well controlled on ART, HIV-positive individuals who had participated in the sleep studies still had elevated brain age,” said Dr. Westover. “We didn’t have enough information to determine the pathways by which HIV increases the BAI, but chronic inflammation appears to be an important factor.”

The findings also demonstrated that comorbidities accounted for roughly a quarter of the effect of HIV on BAI. However, the lack of statistical significance (in part because of the limited sample size) precluded the ability to determine if treating or preventing them might influence the degree to which HIV affects BAI and, in turn, cognitive decline.
 

HIV, sleep EEG, and brain aging

To estimate the effect of HIV on specific EEG features, the investigators again evaluated the total effect, this time replacing BAI with individual sleep EEG as the primary outcome. Among the 34 EEG features significantly altered by HIV, none were observed in the wake state and three were altered in REM (each associated with reduced delta band power). The rest were distributed in non-REM sleep, most notably in the deepest phase, corresponding to relative reductions in delta wave power.

The study findings build on the investigators’ previous research, which demonstrated an association between greater mean BAI and dementia, psychotic disorders, and anxiety/mood disorders in HIV-negative subjects, all of which correlated to attenuated slow-wave sleep.

More research is needed to determine if BAI, as it relates to sleep EEG, can effectively track the risk for cognitive decline among HIV-positive people, and if certain confounders might attenuate or accelerate this risk.

“While our team has not specifically looked at BAI, the findings in this study seem perfectly in line with what we have found with our own research,” Dr. Gamaldo said in an interview. “Not only have we observed a robust association between minimal cognitive deficits and patients’ sleep complaints (despite being virally controlled), but also, the potential value of measuring the architectural sleep features by ambulatory EEG to identify HIV patients’ vulnerability to cognitive decline.”

“BAI is a physiologic, easily repeatable measurement that can be used to track if an intervention is having a good effect,” Dr. Westover said.

Dr. Mukerji concurred, adding that “having a tool that can be used in resource-challenged settings and also be incorporated into longitudinal studies in a patient population with substantial age-related comorbidities, like HIV, would be really helpful.”

Dr. Westover and Dr. Mukerji disclosed no relevant financial relationships. Dr. Gamaldo is a consultant for Jazz Pharmaceuticals, and has received author royalties from UpToDate and honoraria from Medscape CME for content contribution.

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

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

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

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

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

When 42-year-old Danielle Simone Brand started having hormonal migraines, she first turned to cannabidiol (CBD) oil, eventually adding an occasional pull on a prefilled tetrahydrocannabinol (THC) vape for nighttime use. She was careful to avoid THC during work hours. A parenting and cannabis writer, Ms. Brand had more than a cursory background in cannabinoid medicine and had spent time at her local California dispensary discussing various cannabinoid components that might help alleviate her pain.

Anatoliy Sizov/Getty Images

A self-professed “do-it-yourselfer,” Ms. Brand continues to use cannabinoids for her monthly headaches, forgoing any other pain medication. “There are times for conventional medicine in partnership with your doctor, but when it comes to health and wellness, women should be empowered to make decisions and self-experiment,” she said in an interview.

Ms. Brand is not alone. Significant numbers of women are replacing or supplementing prescription medications with cannabinoids, often without consulting their primary care physician, ob.gyn., or other specialist. At times, women have tried to have these conversations, only to be met with silence or worse.

Take Linda Fuller, a 58-year-old yoga instructor from Long Island who says that she uses CBD and THC for chronic sacroiliac pain after a car accident and to alleviate stress-triggered eczema flares. “I’ve had doctors turn their backs on me; I’ve had nurse practitioners walk out on me in the middle of a sentence,” she said in an interview.

Ms. Fuller said her conversion to cannabinoid medicine is relatively new; she never used cannabis recreationally before her accident but now considers it a gift. She doesn’t keep aspirin in the house and refused pain medication immediately after she injured her back.

Diana Krach, a 34-year-old writer from Maryland, says she’s encountered roadblocks about her decision to use cannabinoids for endometriosis and for pain from Crohn’s disease. When she tried to discuss her CBD use with a gastroenterologist, he interrupted her: “Whatever pot you’re smoking isn’t going to work, you’re going on biologics.”

Ms. Krach had not been smoking anything but had turned to a CBD tincture for symptom relief after prescription pain medications failed to help.

Ms. Brand, Ms. Fuller, and Ms. Krach are the tip of the iceberg when it comes to women seeking symptom relief outside the medicine cabinet. A recent survey in the Journal of Women’s Health of almost 1,000 women show that 90% (most between the ages of 35 and 44) had used cannabis and would consider using it to treat gynecologic pain. Roughly 80% said they would consider using it for procedure-related pain or other conditions. Additionally, women have reported using cannabinoids for PTSD, sleep disturbances or insomnia, anxiety, and migraine headaches.

Observational survey data have likewise shown that 80% of women with advanced or recurrent gynecologic malignancies who were prescribed cannabis reported that it was equivalent or superior to other medications for relieving pain, neuropathy, nausea, insomnia, decreased appetite, and anxiety.

In another survey, almost half (45%) of women with gynecologic malignancies who used nonprescribed cannabis for the same symptoms reported that they had reduced their use of prescription narcotics after initiating use of cannabis.
 

The gray zone

There has been a surge in self-reported cannabis use among pregnant women in particular. The National Survey on Drug Use and Health findings for the periods 2002-2003 and 2016-2017 highlight increases in adjusted prevalence rates from 3.4% to 7% in past-month use among pregnant women overall and from 5.7% to 12.1% during the first trimester alone.

“The more that you talk to pregnant women, the more that you realize that a lot are using cannabinoids for something that is basically medicinal, for sleep, for anxiety, or for nausea,” Katrina Mark, MD, an ob.gyn. and associate professor of medicine at the University of Maryland, College Park, said in an interview. “I’m not saying it’s fine to use drugs in pregnancy, but it is a grayer conversation than a lot of colleagues want to believe. Telling women to quit seems foolish since the alternative is to be anxious, don’t sleep, don’t eat, or use a medication that also has risks to it.”

One observational study shows that pregnant women themselves are conflicted. Although the majority believe that cannabis is “natural” and “safe,” compared with prescription drugs, they aren’t entirely in the dark about potential risks. They often express frustration with practitioners’ responses when these topics are broached during office visits. An observational survey among women and practitioners published in 2020 highlights that only half of doctors openly discouraged perinatal cannabis use and that others opted out of the discussion entirely.

This is the experience of many of the women that this news organization spoke with. Ms. Krach pointed out that “there’s a big deficit in listening; the doctor is supposed to be working for our behalf, especially when it comes to reproductive health.”

Dr. Mark believed that a lot of the conversation has been clouded by the illegality of the substance but that cannabinoids deserve as much of a fair chance for discussion and consideration as other medicines, which also carry risks in pregnancy. “There’s literally no evidence that it will work in pregnancy [for these symptoms], but there’s no evidence that it doesn’t, either,” she said in an interview. “When I have this conversation with colleagues who do not share my views, I try to encourage them to look at the actual risks versus the benefits versus the alternatives.”

The ‘entourage effect’

Data supporting cannabinoids have been mostly laboratory based, case based, or observational. However, several well-designed (albeit small) trials have demonstrated efficacy for chronic pain conditions, including neuropathic and headache pain, as well as in Crohn’s disease. Most investigators have concluded that dosage is important and that there is a synergistic interaction between compounds (known as the “entourage effect”) that relates to cannabinoid efficacy or lack thereof, as well as possible adverse effects.

In addition to legality issues, the entourage effect is one of the most important factors related to the medical use of cannabinoids. “There are literally thousands of cultivars of cannabis, each with their own phytocannabinoid and terpenic profiles that may produce distinct therapeutic effects, [so] it is misguided to speak of cannabis in monolithic terms. It is like making broad claims about soup,” wrote coauthor Samoon Ahmad, MD, in Medical Marijuana: A Clinical Handbook.

Additionally, the role that reproductive hormones play is not entirely understood. Reproductive-aged women appear to be more susceptible to a “telescoping” (gender-related progression to dependence) effect in comparison with men. Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, said in an interview. She explained that research has shown that factors such as the degree of exposure, frequency of use, and menses confound this susceptibility.
 

It’s the data

Frustration over cannabinoid therapeutics abound, especially when it comes to data, legal issues, and lack of training. “The feedback that I hear from providers is that there isn’t enough information; we just don’t know enough about it,” Dr. Mark said, “but there is information that we do have, and ignoring it is not beneficial.”

Dr. Cooper concurred. Although she readily acknowledges that data from randomized, placebo-controlled trials are mostly lacking, she says, “There are signals in the literature providing evidence for the utility of cannabis and cannabinoids for pain and some other effects.”

Other practitioners said in an interview that some patients admit to using cannabinoids but that they lack the ample information to guide these patients. By and large, many women equate “natural” with “safe,” and some will experiment on their own to see what works.

Those experiments are not without risk, which is why “it’s just as important for physicians to talk to their patients about cannabis use as it is for patients to be forthcoming about that use,” said Dr. Cooper. “It could have implications on their overall health as well as interactions with other drugs that they’re using.”

That balance from a clinical perspective on cannabis is crucial, wrote coauthor Kenneth Hill, MD, in Medical Marijuana: A Clinical Handbook. “Without it,” he wrote, “the window of opportunity for a patient to accept treatment that she needs may not be open very long.”

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

Plagued by false starts, a few dashed hopes, but with perhaps a glimmer of light on the horizon, the race to find an effective treatment for COVID-19 continues. At last count, more than 300 treatments and 200 vaccines were in preclinical or clinical development (not to mention the numerous existing agents that are being evaluated for repurposing).

There is also a renewed interest in cannabinoid therapeutics — in particular, the nonpsychoactive agent cannabidiol (CBD) and the prospect of its modulating inflammatory and other disease-associated clinical indices, including SARS-CoV-2–induced viral load, hyperinflammation, the cytokine storm, and acute respiratory distress syndrome (ARDS).

Long hobbled by regulatory, political, and financial barriers, CBD’s potential ability to knock back COVID-19–related inflammation might just open doors that have been closed for years to CBD researchers.
 

Why CBD and why now?

CBD and the resulting therapeutics have been plagued by a complicated association with recreational cannabis use. It’s been just 2 years since CBD-based therapeutics moved into mainstream medicine — the US Food and Drug Administration (FDA) approved Epidiolex oral solution for the treatment of Lennox-Gastaut syndrome and Dravet syndrome, and in August, the FDA approved it for tuberous sclerosis complex.

CBD’s mechanism of action has not been fully elucidated, but on the basis of its role in immune responses — well described in research spanning more than two decades — it›s not surprising that cannabinoid researchers have thrown their hats into the COVID-19 drug development ring.

The anti-inflammatory potential of CBD is substantial and appears to be related to the fact that it shares 20 protein targets common to inflammation-related pathways, Jenny Wilkerson, PhD, research assistant professor at the University of Florida School of Pharmacy, Gainesville, Florida, explained to Medscape Medical News.

Among the various trials that are currently recruiting or are underway is one that is slated for completion this fall. CANDIDATE (Cannabidiol for COVID-19 Patients With Mild-to-Moderate COVID-19) is a randomized, controlled, double-blind study led by Brazilian researchers at the University of São Paulo. The study, which began recruitment this past August, enrolled 100 patients, 50 in the active treatment group (who received capsulated CBD 300 mg daily for 14 days plus pharmacologic therapy [antipyretics] and clinical measures) and 50 who received placebo.

The primary outcome is intended to help clarify the potential role of oral CBD for preventing COVID-19 disease progression, modifying disease-associated clinical indices, and modulating inflammatory parameters, such as the cytokine storm, according to lead investigator Jose Alexandre de Souza Crippa, MD, PhD, professor of neuropsychology at the Ribeirao Preto Medical School at the University of São Paulo in Brazil, in the description of the study on clinicaltrials.gov. Crippa declined to provide any additional information about the trial in an email to Medscape Medical News.
 

Calming or preventing the storm

While Crippa and colleagues wrap up their CBD trial in South America, several North American and Canadian researchers are seeking to clarify and address one of the most therapeutically challenging aspects of SARS-CoV-2 infection — the lung macrophage–orchestrated hyperinflammatory response.

Although hyperinflammation is not unique to SARS-CoV-2 infection, disease severity and COVID-19–related mortality have been linked to this rapid and prolonged surge of inflammatory cytokines (eg, interleukin 6 [IL-6], IL-10, tumor necrosis factors [TNF], and chemokines) and the cytokine storm.

“When you stimulate CB2 receptors (involved in fighting inflammation), you get a release of the same inflammatory cytokines that are involved in COVID,” Cecilia Costiniuk, MD, associate professor and researcher at the Research Institute of the McGill University Health Center, Montreal, Canada, told Medscape Medical News.

“So, if you can act on this receptor, you might be able to reduce the release of those damaging cytokines that are causing ARDS, lung damage, etc,” she explained. Targeting these inflammatory mediators has been a key strategy in research aimed at reducing COVID-19 severity and related mortality, which is where CBD comes into play.

“CBD is a very powerful immune regulator. It keeps the [immune] engine on, but it doesn’t push the gas pedal, and it doesn’t push the brake completely,” Babak Baban, PhD, professor and immunologist at the Dental College of Georgia at Augusta University, told Medscape Medical News.

To explore the effectiveness of CBD in reducing hyperactivated inflammatory reactions, Baban and colleagues examined the potential of CBD to ameliorate ARDS in a murine model. The group divided wild-type male mice into sham, control, and treatment groups.

The sham group received intranasal phosphate buffered saline; the treatment and control groups received a polyriboinosinic:polycytidylic acid (poly I:C) double-stranded RNA analogue (100 mcg daily for 3 days) to simulate the cytokine storm and clinical ARDS symptoms.

Following the second poly I:C dose, the treatment group received CBD 5 mg/kg intraperitoneally every other day for 6 days. The mice were sacrificed on day 8.

The study results, published in July in Cannabis and Cannabinoid Research, first confirmed that the poly I:C model simulated the cytokine storm in ARDS, reducing blood oxygen saturation by as much as 10% (from ±81.6% to ±72.2%).

Intraperitoneally administered CBD appeared to reverse these ARDS-like trends. “We observed a significant improvement in severe lymphopenia, a mild decline in the ratio of neutrophils to T cells, and significant reductions in levels of [inflammatory and immune factors] IL-6, IFN-gamma [interferon gamma], and in TNF-alpha after the second CBD dose,” Baban said.

There was also a marked downregulation in infiltrating neutrophils and macrophages in the lung, leading to partial restoration of lung morphology and structure. The investigators write that this suggests “a counter inflammatory role for CBD to limit ARDS progression.”

Additional findings from a follow-up study published in mid-October “provide strong data that CBD may partially assert its beneficial and protective impact through its regulation of the apelin peptide,” wrote Baban in an email to Medscape Medical News.

“Apelin may also be a reliable biomarker for early diagnosis of ARDS in general, and in COVID-19 in particular,” he wrote.

Questions remain concerning dose response and whether CBD alone or in combination with other phytocannabinoids is more effective for treating COVID-19. Timing is likewise unclear.

Baban explained that as a result of the biphasic nature of COVID-19, the “sweet spot” appears to be just before the innate immune response progresses into an inflammation-driven response and fibrotic lung damage occurs.

But Wilkerson isn’t as convinced. She said that as with a thermostat, the endocannabinoid system needs tweaking to get it in the right place, that is, to achieve immune homeostasis. The COVID cytokine storm is highly unpredictable, she added, saying, “Right now, the timing for controlling the COVID cytokine storm is really a moving target.”
 

Is safety a concern?

Safety questions are expected to arise, especially in relation to COVID-19. CBD is not risk free, and one size does not fit all. Human CBD studies report gastrointestinal and somnolent effects, as well as drug-drug interactions.

Findings from a recent systematic review of randomized, controlled CBD trials support overall tolerability, suggesting that serious adverse events are rare. Such events are believed to be related to drug-drug interactions rather than to CBD itself. On the flip side, it is nonintoxicating, and there does not appear to be potential for abuse.

“It’s generally well tolerated,” Wilkerson said. “There’ve now been several clinical trials in numerous patient population settings where basically the only time you really start to have issues is where you have patients on very select agents. But this is where a pharmacist would come into play.”

Costiniuk agreed: “Just because it’s cannabis, it doesn’t mean that there’s going to be strange or unusual effects; these people [ie, those with severe COVID-19] are in the hospital and monitored very closely.”
 

Delving into the weeds: What’s next?

Although non-COVID-19 cannabinoid researchers have encountered regulatory roadblocks, several research groups that have had the prescience to dive in at the right time are gaining momentum.

Baban’s team has connected with one of the nation’s few academic laboratories authorized to work with the SARS-CoV-2 virus and are awaiting protocol approval so that they can reproduce their research, this time using two CBD formulations (injectable and inhaled).

If findings are positive, they will move forward quickly to meet with the FDA, Baban said, adding that the team is also collaborating with two organizations to conduct human clinical trials in hopes of pushing up timing.

The initial article caught the eye of the World Health Organization, which included it in its global literature on the coronavirus resource section.

Israeli researchers have also been quite busy. InnoCan Pharma and Tel Aviv University are collaborating to explore the potential for CBD-loaded exosomes (minute extracellular particles that mediate intracellular communication, including via innate and adaptive immune responses). The group plans to use these loaded exosomes to target and facilitate recovery of COVID-19–damaged lung cells.

From a broader perspective, the prospects for harnessing cannabinoids for immune modulation will be more thoroughly explored in a special issue of Cannabis and Cannabinoid Research, which has extended its current call for papers, studies, abstracts, and conference proceedings until the end of December.

Like many of the therapeutic strategies under investigation for the treatment of COVID-19, studies in CBD may continue to raise more questions than answers.

Still, Wilkerson is optimistic. “Taken together, these studies along with countless others suggest that the complex pharmacophore of Cannabis sativa may hold therapeutic utility to treat lung inflammation, such as what is seen in a COVID-19 cytokine storm,» she told Medscape Medical News. “I’m very excited to see what comes out of the research.”

Baban, Wilkerson, and Costiniuk have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Plagued by false starts, a few dashed hopes, but with perhaps a glimmer of light on the horizon, the race to find an effective treatment for COVID-19 continues. At last count, more than 300 treatments and 200 vaccines were in preclinical or clinical development (not to mention the numerous existing agents that are being evaluated for repurposing).

There is also a renewed interest in cannabinoid therapeutics — in particular, the nonpsychoactive agent cannabidiol (CBD) and the prospect of its modulating inflammatory and other disease-associated clinical indices, including SARS-CoV-2–induced viral load, hyperinflammation, the cytokine storm, and acute respiratory distress syndrome (ARDS).

Long hobbled by regulatory, political, and financial barriers, CBD’s potential ability to knock back COVID-19–related inflammation might just open doors that have been closed for years to CBD researchers.
 

Why CBD and why now?

CBD and the resulting therapeutics have been plagued by a complicated association with recreational cannabis use. It’s been just 2 years since CBD-based therapeutics moved into mainstream medicine — the US Food and Drug Administration (FDA) approved Epidiolex oral solution for the treatment of Lennox-Gastaut syndrome and Dravet syndrome, and in August, the FDA approved it for tuberous sclerosis complex.

CBD’s mechanism of action has not been fully elucidated, but on the basis of its role in immune responses — well described in research spanning more than two decades — it›s not surprising that cannabinoid researchers have thrown their hats into the COVID-19 drug development ring.

The anti-inflammatory potential of CBD is substantial and appears to be related to the fact that it shares 20 protein targets common to inflammation-related pathways, Jenny Wilkerson, PhD, research assistant professor at the University of Florida School of Pharmacy, Gainesville, Florida, explained to Medscape Medical News.

Among the various trials that are currently recruiting or are underway is one that is slated for completion this fall. CANDIDATE (Cannabidiol for COVID-19 Patients With Mild-to-Moderate COVID-19) is a randomized, controlled, double-blind study led by Brazilian researchers at the University of São Paulo. The study, which began recruitment this past August, enrolled 100 patients, 50 in the active treatment group (who received capsulated CBD 300 mg daily for 14 days plus pharmacologic therapy [antipyretics] and clinical measures) and 50 who received placebo.

The primary outcome is intended to help clarify the potential role of oral CBD for preventing COVID-19 disease progression, modifying disease-associated clinical indices, and modulating inflammatory parameters, such as the cytokine storm, according to lead investigator Jose Alexandre de Souza Crippa, MD, PhD, professor of neuropsychology at the Ribeirao Preto Medical School at the University of São Paulo in Brazil, in the description of the study on clinicaltrials.gov. Crippa declined to provide any additional information about the trial in an email to Medscape Medical News.
 

Calming or preventing the storm

While Crippa and colleagues wrap up their CBD trial in South America, several North American and Canadian researchers are seeking to clarify and address one of the most therapeutically challenging aspects of SARS-CoV-2 infection — the lung macrophage–orchestrated hyperinflammatory response.

Although hyperinflammation is not unique to SARS-CoV-2 infection, disease severity and COVID-19–related mortality have been linked to this rapid and prolonged surge of inflammatory cytokines (eg, interleukin 6 [IL-6], IL-10, tumor necrosis factors [TNF], and chemokines) and the cytokine storm.

“When you stimulate CB2 receptors (involved in fighting inflammation), you get a release of the same inflammatory cytokines that are involved in COVID,” Cecilia Costiniuk, MD, associate professor and researcher at the Research Institute of the McGill University Health Center, Montreal, Canada, told Medscape Medical News.

“So, if you can act on this receptor, you might be able to reduce the release of those damaging cytokines that are causing ARDS, lung damage, etc,” she explained. Targeting these inflammatory mediators has been a key strategy in research aimed at reducing COVID-19 severity and related mortality, which is where CBD comes into play.

“CBD is a very powerful immune regulator. It keeps the [immune] engine on, but it doesn’t push the gas pedal, and it doesn’t push the brake completely,” Babak Baban, PhD, professor and immunologist at the Dental College of Georgia at Augusta University, told Medscape Medical News.

To explore the effectiveness of CBD in reducing hyperactivated inflammatory reactions, Baban and colleagues examined the potential of CBD to ameliorate ARDS in a murine model. The group divided wild-type male mice into sham, control, and treatment groups.

The sham group received intranasal phosphate buffered saline; the treatment and control groups received a polyriboinosinic:polycytidylic acid (poly I:C) double-stranded RNA analogue (100 mcg daily for 3 days) to simulate the cytokine storm and clinical ARDS symptoms.

Following the second poly I:C dose, the treatment group received CBD 5 mg/kg intraperitoneally every other day for 6 days. The mice were sacrificed on day 8.

The study results, published in July in Cannabis and Cannabinoid Research, first confirmed that the poly I:C model simulated the cytokine storm in ARDS, reducing blood oxygen saturation by as much as 10% (from ±81.6% to ±72.2%).

Intraperitoneally administered CBD appeared to reverse these ARDS-like trends. “We observed a significant improvement in severe lymphopenia, a mild decline in the ratio of neutrophils to T cells, and significant reductions in levels of [inflammatory and immune factors] IL-6, IFN-gamma [interferon gamma], and in TNF-alpha after the second CBD dose,” Baban said.

There was also a marked downregulation in infiltrating neutrophils and macrophages in the lung, leading to partial restoration of lung morphology and structure. The investigators write that this suggests “a counter inflammatory role for CBD to limit ARDS progression.”

Additional findings from a follow-up study published in mid-October “provide strong data that CBD may partially assert its beneficial and protective impact through its regulation of the apelin peptide,” wrote Baban in an email to Medscape Medical News.

“Apelin may also be a reliable biomarker for early diagnosis of ARDS in general, and in COVID-19 in particular,” he wrote.

Questions remain concerning dose response and whether CBD alone or in combination with other phytocannabinoids is more effective for treating COVID-19. Timing is likewise unclear.

Baban explained that as a result of the biphasic nature of COVID-19, the “sweet spot” appears to be just before the innate immune response progresses into an inflammation-driven response and fibrotic lung damage occurs.

But Wilkerson isn’t as convinced. She said that as with a thermostat, the endocannabinoid system needs tweaking to get it in the right place, that is, to achieve immune homeostasis. The COVID cytokine storm is highly unpredictable, she added, saying, “Right now, the timing for controlling the COVID cytokine storm is really a moving target.”
 

Is safety a concern?

Safety questions are expected to arise, especially in relation to COVID-19. CBD is not risk free, and one size does not fit all. Human CBD studies report gastrointestinal and somnolent effects, as well as drug-drug interactions.

Findings from a recent systematic review of randomized, controlled CBD trials support overall tolerability, suggesting that serious adverse events are rare. Such events are believed to be related to drug-drug interactions rather than to CBD itself. On the flip side, it is nonintoxicating, and there does not appear to be potential for abuse.

“It’s generally well tolerated,” Wilkerson said. “There’ve now been several clinical trials in numerous patient population settings where basically the only time you really start to have issues is where you have patients on very select agents. But this is where a pharmacist would come into play.”

Costiniuk agreed: “Just because it’s cannabis, it doesn’t mean that there’s going to be strange or unusual effects; these people [ie, those with severe COVID-19] are in the hospital and monitored very closely.”
 

Delving into the weeds: What’s next?

Although non-COVID-19 cannabinoid researchers have encountered regulatory roadblocks, several research groups that have had the prescience to dive in at the right time are gaining momentum.

Baban’s team has connected with one of the nation’s few academic laboratories authorized to work with the SARS-CoV-2 virus and are awaiting protocol approval so that they can reproduce their research, this time using two CBD formulations (injectable and inhaled).

If findings are positive, they will move forward quickly to meet with the FDA, Baban said, adding that the team is also collaborating with two organizations to conduct human clinical trials in hopes of pushing up timing.

The initial article caught the eye of the World Health Organization, which included it in its global literature on the coronavirus resource section.

Israeli researchers have also been quite busy. InnoCan Pharma and Tel Aviv University are collaborating to explore the potential for CBD-loaded exosomes (minute extracellular particles that mediate intracellular communication, including via innate and adaptive immune responses). The group plans to use these loaded exosomes to target and facilitate recovery of COVID-19–damaged lung cells.

From a broader perspective, the prospects for harnessing cannabinoids for immune modulation will be more thoroughly explored in a special issue of Cannabis and Cannabinoid Research, which has extended its current call for papers, studies, abstracts, and conference proceedings until the end of December.

Like many of the therapeutic strategies under investigation for the treatment of COVID-19, studies in CBD may continue to raise more questions than answers.

Still, Wilkerson is optimistic. “Taken together, these studies along with countless others suggest that the complex pharmacophore of Cannabis sativa may hold therapeutic utility to treat lung inflammation, such as what is seen in a COVID-19 cytokine storm,» she told Medscape Medical News. “I’m very excited to see what comes out of the research.”

Baban, Wilkerson, and Costiniuk have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Plagued by false starts, a few dashed hopes, but with perhaps a glimmer of light on the horizon, the race to find an effective treatment for COVID-19 continues. At last count, more than 300 treatments and 200 vaccines were in preclinical or clinical development (not to mention the numerous existing agents that are being evaluated for repurposing).

There is also a renewed interest in cannabinoid therapeutics — in particular, the nonpsychoactive agent cannabidiol (CBD) and the prospect of its modulating inflammatory and other disease-associated clinical indices, including SARS-CoV-2–induced viral load, hyperinflammation, the cytokine storm, and acute respiratory distress syndrome (ARDS).

Long hobbled by regulatory, political, and financial barriers, CBD’s potential ability to knock back COVID-19–related inflammation might just open doors that have been closed for years to CBD researchers.
 

Why CBD and why now?

CBD and the resulting therapeutics have been plagued by a complicated association with recreational cannabis use. It’s been just 2 years since CBD-based therapeutics moved into mainstream medicine — the US Food and Drug Administration (FDA) approved Epidiolex oral solution for the treatment of Lennox-Gastaut syndrome and Dravet syndrome, and in August, the FDA approved it for tuberous sclerosis complex.

CBD’s mechanism of action has not been fully elucidated, but on the basis of its role in immune responses — well described in research spanning more than two decades — it›s not surprising that cannabinoid researchers have thrown their hats into the COVID-19 drug development ring.

The anti-inflammatory potential of CBD is substantial and appears to be related to the fact that it shares 20 protein targets common to inflammation-related pathways, Jenny Wilkerson, PhD, research assistant professor at the University of Florida School of Pharmacy, Gainesville, Florida, explained to Medscape Medical News.

Among the various trials that are currently recruiting or are underway is one that is slated for completion this fall. CANDIDATE (Cannabidiol for COVID-19 Patients With Mild-to-Moderate COVID-19) is a randomized, controlled, double-blind study led by Brazilian researchers at the University of São Paulo. The study, which began recruitment this past August, enrolled 100 patients, 50 in the active treatment group (who received capsulated CBD 300 mg daily for 14 days plus pharmacologic therapy [antipyretics] and clinical measures) and 50 who received placebo.

The primary outcome is intended to help clarify the potential role of oral CBD for preventing COVID-19 disease progression, modifying disease-associated clinical indices, and modulating inflammatory parameters, such as the cytokine storm, according to lead investigator Jose Alexandre de Souza Crippa, MD, PhD, professor of neuropsychology at the Ribeirao Preto Medical School at the University of São Paulo in Brazil, in the description of the study on clinicaltrials.gov. Crippa declined to provide any additional information about the trial in an email to Medscape Medical News.
 

Calming or preventing the storm

While Crippa and colleagues wrap up their CBD trial in South America, several North American and Canadian researchers are seeking to clarify and address one of the most therapeutically challenging aspects of SARS-CoV-2 infection — the lung macrophage–orchestrated hyperinflammatory response.

Although hyperinflammation is not unique to SARS-CoV-2 infection, disease severity and COVID-19–related mortality have been linked to this rapid and prolonged surge of inflammatory cytokines (eg, interleukin 6 [IL-6], IL-10, tumor necrosis factors [TNF], and chemokines) and the cytokine storm.

“When you stimulate CB2 receptors (involved in fighting inflammation), you get a release of the same inflammatory cytokines that are involved in COVID,” Cecilia Costiniuk, MD, associate professor and researcher at the Research Institute of the McGill University Health Center, Montreal, Canada, told Medscape Medical News.

“So, if you can act on this receptor, you might be able to reduce the release of those damaging cytokines that are causing ARDS, lung damage, etc,” she explained. Targeting these inflammatory mediators has been a key strategy in research aimed at reducing COVID-19 severity and related mortality, which is where CBD comes into play.

“CBD is a very powerful immune regulator. It keeps the [immune] engine on, but it doesn’t push the gas pedal, and it doesn’t push the brake completely,” Babak Baban, PhD, professor and immunologist at the Dental College of Georgia at Augusta University, told Medscape Medical News.

To explore the effectiveness of CBD in reducing hyperactivated inflammatory reactions, Baban and colleagues examined the potential of CBD to ameliorate ARDS in a murine model. The group divided wild-type male mice into sham, control, and treatment groups.

The sham group received intranasal phosphate buffered saline; the treatment and control groups received a polyriboinosinic:polycytidylic acid (poly I:C) double-stranded RNA analogue (100 mcg daily for 3 days) to simulate the cytokine storm and clinical ARDS symptoms.

Following the second poly I:C dose, the treatment group received CBD 5 mg/kg intraperitoneally every other day for 6 days. The mice were sacrificed on day 8.

The study results, published in July in Cannabis and Cannabinoid Research, first confirmed that the poly I:C model simulated the cytokine storm in ARDS, reducing blood oxygen saturation by as much as 10% (from ±81.6% to ±72.2%).

Intraperitoneally administered CBD appeared to reverse these ARDS-like trends. “We observed a significant improvement in severe lymphopenia, a mild decline in the ratio of neutrophils to T cells, and significant reductions in levels of [inflammatory and immune factors] IL-6, IFN-gamma [interferon gamma], and in TNF-alpha after the second CBD dose,” Baban said.

There was also a marked downregulation in infiltrating neutrophils and macrophages in the lung, leading to partial restoration of lung morphology and structure. The investigators write that this suggests “a counter inflammatory role for CBD to limit ARDS progression.”

Additional findings from a follow-up study published in mid-October “provide strong data that CBD may partially assert its beneficial and protective impact through its regulation of the apelin peptide,” wrote Baban in an email to Medscape Medical News.

“Apelin may also be a reliable biomarker for early diagnosis of ARDS in general, and in COVID-19 in particular,” he wrote.

Questions remain concerning dose response and whether CBD alone or in combination with other phytocannabinoids is more effective for treating COVID-19. Timing is likewise unclear.

Baban explained that as a result of the biphasic nature of COVID-19, the “sweet spot” appears to be just before the innate immune response progresses into an inflammation-driven response and fibrotic lung damage occurs.

But Wilkerson isn’t as convinced. She said that as with a thermostat, the endocannabinoid system needs tweaking to get it in the right place, that is, to achieve immune homeostasis. The COVID cytokine storm is highly unpredictable, she added, saying, “Right now, the timing for controlling the COVID cytokine storm is really a moving target.”
 

Is safety a concern?

Safety questions are expected to arise, especially in relation to COVID-19. CBD is not risk free, and one size does not fit all. Human CBD studies report gastrointestinal and somnolent effects, as well as drug-drug interactions.

Findings from a recent systematic review of randomized, controlled CBD trials support overall tolerability, suggesting that serious adverse events are rare. Such events are believed to be related to drug-drug interactions rather than to CBD itself. On the flip side, it is nonintoxicating, and there does not appear to be potential for abuse.

“It’s generally well tolerated,” Wilkerson said. “There’ve now been several clinical trials in numerous patient population settings where basically the only time you really start to have issues is where you have patients on very select agents. But this is where a pharmacist would come into play.”

Costiniuk agreed: “Just because it’s cannabis, it doesn’t mean that there’s going to be strange or unusual effects; these people [ie, those with severe COVID-19] are in the hospital and monitored very closely.”
 

Delving into the weeds: What’s next?

Although non-COVID-19 cannabinoid researchers have encountered regulatory roadblocks, several research groups that have had the prescience to dive in at the right time are gaining momentum.

Baban’s team has connected with one of the nation’s few academic laboratories authorized to work with the SARS-CoV-2 virus and are awaiting protocol approval so that they can reproduce their research, this time using two CBD formulations (injectable and inhaled).

If findings are positive, they will move forward quickly to meet with the FDA, Baban said, adding that the team is also collaborating with two organizations to conduct human clinical trials in hopes of pushing up timing.

The initial article caught the eye of the World Health Organization, which included it in its global literature on the coronavirus resource section.

Israeli researchers have also been quite busy. InnoCan Pharma and Tel Aviv University are collaborating to explore the potential for CBD-loaded exosomes (minute extracellular particles that mediate intracellular communication, including via innate and adaptive immune responses). The group plans to use these loaded exosomes to target and facilitate recovery of COVID-19–damaged lung cells.

From a broader perspective, the prospects for harnessing cannabinoids for immune modulation will be more thoroughly explored in a special issue of Cannabis and Cannabinoid Research, which has extended its current call for papers, studies, abstracts, and conference proceedings until the end of December.

Like many of the therapeutic strategies under investigation for the treatment of COVID-19, studies in CBD may continue to raise more questions than answers.

Still, Wilkerson is optimistic. “Taken together, these studies along with countless others suggest that the complex pharmacophore of Cannabis sativa may hold therapeutic utility to treat lung inflammation, such as what is seen in a COVID-19 cytokine storm,» she told Medscape Medical News. “I’m very excited to see what comes out of the research.”

Baban, Wilkerson, and Costiniuk have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.