Bianca Nogrady

Brisbane, Australia – Most cases of virologic failure on dolutegravir treatment for HIV are likely due to adherence problems and more time on treatment is needed before switching to another drug, according to new data from the ADVANCE trial.
 

“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” said Andrew Hill, MD, from the department of pharmacology and therapeutics at the University of Liverpool, England.

The new data was presented here at the International AIDS Society conference on HIV Science. The ADVANCE trial is a three-arm randomized study involving 1,053 treatment-naive individuals comparing two triple-therapy combinations — dolutegravir, emtricitabine, and one of two tenofovir prodrugs – with a standard care regimen of tenofovir disoproxil fumarate, emtricitabine, and efavirenz.

Although the usual approach for someone in a clinical trial who experiences elevations in HIV RNA levels while on a dolutegravir-based treatment is to switch them to another therapy, the ADVANCE investigators opted for a different strategy.

“We actually continued treatment despite high viral load, and we didn’t have standard discontinuation preferences,” Dr. Hill said at the meeting. They instead provided counseling about adherence, which gave an opportunity to examine viral resuppression rates in participants in both the dolutegravir and efavirenz arms.

This revealed that 95% of patients in the two dolutegravir arms of the study were able to achieve resuppression of their viral load – defined as below 50 viral RNA copies per mL – without any emergence of resistance.
 

The guidelines

Current World Health Organization guidelines recommend that anyone whose viral load goes above 1,000 copies per mL who is on a non-nucleoside reverse transcriptase inhibitor such as efavirenz should be switched to an appropriate regimen.

Those who experience viremia on an integrase inhibitor such as dolutegravir should receive adherence counseling, have a repeat viral load test done in 3 months, and – if their viral load is still elevated – be switched to another regimen.

Dr. Hill and his team were examining how this might play out in a clinical trial setting and they found that there were a similar number of episodes of initial virologic failure in both the dolutegravir and efavirenz groups.

But after adherence counseling, testing for resistance and – if no resistance was evident – continuation with treatment, they saw differences emerge between the two groups.

“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” he said.
 

Time to viral resuppression

At 24 weeks after restarting treatment, 88% of people in the dolutegravir group had resuppressed their viral RNA, compared with 46% of people in the efavirenz group. At 48 weeks, those figures were 95% and 66%, respectively.

Dr. Hill pointed out that a significant number of people were lost to follow-up after virologic failure, and genotyping was not performed at baseline.

We addressed the question of how much adherence counseling should be undertaken in people who experienced viremia while on dolutegravir therapy, Dr. Hill said, particularly as there were often very good reasons for lack of adherence, such as homelessness.

“If you can get through those difficult phases, people can go back on their meds,” he said in an interview. “It’s almost a sociological problem rather than a clinical issue.”

And with efavirenz and the lower rates of resuppression observed in the study, Dr. Hill said it was a more fragile drug, so viremia therefore provided the opportunity for resistance to emerge, “and then once the resistant virus is there, you can’t get virus undetectable.”

Laura Waters, MD, a genitourinary and HIV medicine consultant at the Mortimer Market Centre in London, who was not involved in the study, said the results support recommendations to give people on drugs such as dolutegravir, which have a high genetic barrier to resistance, more time to improve their adherence before switching to another therapy.

“Although it provides that reassuring proof of concept, it doesn’t negate the importance of having to continue to monitor, because nothing is infallible,” she told this news organization. “We’ve talked about high-barrier drugs in the past, and you do start seeing resistance emerge.”

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

Brisbane, Australia – Most cases of virologic failure on dolutegravir treatment for HIV are likely due to adherence problems and more time on treatment is needed before switching to another drug, according to new data from the ADVANCE trial.
 

“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” said Andrew Hill, MD, from the department of pharmacology and therapeutics at the University of Liverpool, England.

The new data was presented here at the International AIDS Society conference on HIV Science. The ADVANCE trial is a three-arm randomized study involving 1,053 treatment-naive individuals comparing two triple-therapy combinations — dolutegravir, emtricitabine, and one of two tenofovir prodrugs – with a standard care regimen of tenofovir disoproxil fumarate, emtricitabine, and efavirenz.

Although the usual approach for someone in a clinical trial who experiences elevations in HIV RNA levels while on a dolutegravir-based treatment is to switch them to another therapy, the ADVANCE investigators opted for a different strategy.

“We actually continued treatment despite high viral load, and we didn’t have standard discontinuation preferences,” Dr. Hill said at the meeting. They instead provided counseling about adherence, which gave an opportunity to examine viral resuppression rates in participants in both the dolutegravir and efavirenz arms.

This revealed that 95% of patients in the two dolutegravir arms of the study were able to achieve resuppression of their viral load – defined as below 50 viral RNA copies per mL – without any emergence of resistance.
 

The guidelines

Current World Health Organization guidelines recommend that anyone whose viral load goes above 1,000 copies per mL who is on a non-nucleoside reverse transcriptase inhibitor such as efavirenz should be switched to an appropriate regimen.

Those who experience viremia on an integrase inhibitor such as dolutegravir should receive adherence counseling, have a repeat viral load test done in 3 months, and – if their viral load is still elevated – be switched to another regimen.

Dr. Hill and his team were examining how this might play out in a clinical trial setting and they found that there were a similar number of episodes of initial virologic failure in both the dolutegravir and efavirenz groups.

But after adherence counseling, testing for resistance and – if no resistance was evident – continuation with treatment, they saw differences emerge between the two groups.

“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” he said.
 

Time to viral resuppression

At 24 weeks after restarting treatment, 88% of people in the dolutegravir group had resuppressed their viral RNA, compared with 46% of people in the efavirenz group. At 48 weeks, those figures were 95% and 66%, respectively.

Dr. Hill pointed out that a significant number of people were lost to follow-up after virologic failure, and genotyping was not performed at baseline.

We addressed the question of how much adherence counseling should be undertaken in people who experienced viremia while on dolutegravir therapy, Dr. Hill said, particularly as there were often very good reasons for lack of adherence, such as homelessness.

“If you can get through those difficult phases, people can go back on their meds,” he said in an interview. “It’s almost a sociological problem rather than a clinical issue.”

And with efavirenz and the lower rates of resuppression observed in the study, Dr. Hill said it was a more fragile drug, so viremia therefore provided the opportunity for resistance to emerge, “and then once the resistant virus is there, you can’t get virus undetectable.”

Laura Waters, MD, a genitourinary and HIV medicine consultant at the Mortimer Market Centre in London, who was not involved in the study, said the results support recommendations to give people on drugs such as dolutegravir, which have a high genetic barrier to resistance, more time to improve their adherence before switching to another therapy.

“Although it provides that reassuring proof of concept, it doesn’t negate the importance of having to continue to monitor, because nothing is infallible,” she told this news organization. “We’ve talked about high-barrier drugs in the past, and you do start seeing resistance emerge.”

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

Brisbane, Australia – Most cases of virologic failure on dolutegravir treatment for HIV are likely due to adherence problems and more time on treatment is needed before switching to another drug, according to new data from the ADVANCE trial.
 

“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” said Andrew Hill, MD, from the department of pharmacology and therapeutics at the University of Liverpool, England.

The new data was presented here at the International AIDS Society conference on HIV Science. The ADVANCE trial is a three-arm randomized study involving 1,053 treatment-naive individuals comparing two triple-therapy combinations — dolutegravir, emtricitabine, and one of two tenofovir prodrugs – with a standard care regimen of tenofovir disoproxil fumarate, emtricitabine, and efavirenz.

Although the usual approach for someone in a clinical trial who experiences elevations in HIV RNA levels while on a dolutegravir-based treatment is to switch them to another therapy, the ADVANCE investigators opted for a different strategy.

“We actually continued treatment despite high viral load, and we didn’t have standard discontinuation preferences,” Dr. Hill said at the meeting. They instead provided counseling about adherence, which gave an opportunity to examine viral resuppression rates in participants in both the dolutegravir and efavirenz arms.

This revealed that 95% of patients in the two dolutegravir arms of the study were able to achieve resuppression of their viral load – defined as below 50 viral RNA copies per mL – without any emergence of resistance.
 

The guidelines

Current World Health Organization guidelines recommend that anyone whose viral load goes above 1,000 copies per mL who is on a non-nucleoside reverse transcriptase inhibitor such as efavirenz should be switched to an appropriate regimen.

Those who experience viremia on an integrase inhibitor such as dolutegravir should receive adherence counseling, have a repeat viral load test done in 3 months, and – if their viral load is still elevated – be switched to another regimen.

Dr. Hill and his team were examining how this might play out in a clinical trial setting and they found that there were a similar number of episodes of initial virologic failure in both the dolutegravir and efavirenz groups.

But after adherence counseling, testing for resistance and – if no resistance was evident – continuation with treatment, they saw differences emerge between the two groups.

“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” he said.
 

Time to viral resuppression

At 24 weeks after restarting treatment, 88% of people in the dolutegravir group had resuppressed their viral RNA, compared with 46% of people in the efavirenz group. At 48 weeks, those figures were 95% and 66%, respectively.

Dr. Hill pointed out that a significant number of people were lost to follow-up after virologic failure, and genotyping was not performed at baseline.

We addressed the question of how much adherence counseling should be undertaken in people who experienced viremia while on dolutegravir therapy, Dr. Hill said, particularly as there were often very good reasons for lack of adherence, such as homelessness.

“If you can get through those difficult phases, people can go back on their meds,” he said in an interview. “It’s almost a sociological problem rather than a clinical issue.”

And with efavirenz and the lower rates of resuppression observed in the study, Dr. Hill said it was a more fragile drug, so viremia therefore provided the opportunity for resistance to emerge, “and then once the resistant virus is there, you can’t get virus undetectable.”

Laura Waters, MD, a genitourinary and HIV medicine consultant at the Mortimer Market Centre in London, who was not involved in the study, said the results support recommendations to give people on drugs such as dolutegravir, which have a high genetic barrier to resistance, more time to improve their adherence before switching to another therapy.

“Although it provides that reassuring proof of concept, it doesn’t negate the importance of having to continue to monitor, because nothing is infallible,” she told this news organization. “We’ve talked about high-barrier drugs in the past, and you do start seeing resistance emerge.”

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

Brisbane, Australia – Concerns about lower lymphocyte levels in HIV with the once-daily oral drug islatravir in combination with doravirine changed the trajectory of clinical trial plans that are now back on track, according to investigators.

The nucleoside reverse transcriptase translocation inhibitor hit a roadblock in December 2021 when the U.S. Food and Drug Administration put a hold on investigational new drug applications for both the oral and implant formulations of islatravir after some patients in clinical trials showed decreases in total lymphocyte and CD4+ cell counts.

A phase 3, double-blind, randomized, controlled trial was underway at the time of once-daily islatravir (0.75 mg) in combination with 100 mg doravirine, compared with bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) as initial therapy for HIV infection in treatment-naïve individuals. Recruitment was stopped, 83 participants short of the planned 680, but the trial could continue the full 48 weeks.

Jürgen Rockstroh, MD, professor of medicine and head of the HIV Outpatient Clinic at the University of Bonn, Germany, presented the latest results from that trial of 597 patients at the International AIDS Society conference on HIV Science.

At week 48 after starting therapy, 88.9% of participants in the islatravir and doravirine arm and 88.3% of patients in the B/F/TAF arm achieved the primary outcome of HIV-1 RNA levels below 50 copies/mL.

One patient treated with islatravir and doravirine and four patients taking B/F/TAF experienced virologic failure.

Dr. Rockstroh told the conference the patient who developed viremia with the new islatravir combination had very high viral load at baseline but showed a rapid response to treatment, which reduced his viral load down to around 1,200 copies/mL by week 4.

However, by week 24, his islatravir concentration had reduced below detectable levels, suggesting a problem with adherence. His viral load increased again, and three treatment-resistant mutations were detected.

While both arms of the study showed a significant increase in CD4+ T cell counts, Dr. Rockstroh pointed out that some individuals in the islatravir and doravirine arm had a lower absolute increase in lymphocyte counts at week 48.

Overall, the mean change in CD4+ T cell counts was 182 cells/mL in the islatravir and doravirine group, compared with 234 cells/mL in the B/F/TAF group.

More patients in the islatravir combination arm discontinued treatment due to a decrease in CD4+ T cell or total lymphocyte counts – 5.4%, compared with 2% in the B/F/TAF arm, however.

“These changes in lymphocyte counts did not lead to any difference in the amount of infection-related adverse events, which happened in both arms in relatively comparable percentages,” Dr. Rockstroh said at the conference.
 

New lower dose

Because of persistent concerns about the impact on CD4+ T cells and total lymphocytes, Dr. Rockstroh said another phase 3 trial is now underway using a lower 0.25 mg dose of islatravir, again combined with 100 mg doravirine, in people who are treatment-naïve and virologically suppressed.

The study also examined the impact of both treatments on weight gain and found the mean change in weight was similar between both arms – 3.45 kg gain in those on islatravir with doravirine and 3.32 kg gain in those on B/F/TAF, which was not significantly different.

There are several important reasons it is a good idea to have more treatment options available for people with HIV, Dr. Rockstroh said in an interview.

With integrase inhibitors potentially interfering with metabolic health, weight gain, hypertension, insulin resistance, and possible diabetes, “I think it’s wise that we at least have alternative strategies,” he said.

James McMahon, MD, PhD, an infectious diseases physician and head of the Infectious Diseases Clinical Research Unit at the Alfred Hospital and Monash University in Melbourne, said there is always a need for new HIV treatments, particularly ones that are more powerful.

“Whenever you get a drug that’s potent at low dose, it means you can have smaller pills, [and] you can then consider giving more of it in long-acting formulations,” Dr. McMahon said.

He pointed out that the study did not show any signal of increased infections with the lower CD4+ T cell counts in the islatravir and doravirine arm, “but that difference is enough to raise that concern that it’s not ideal, and it should be moved forward with a lower dose, which is what they’ve done.”

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

Brisbane, Australia – Concerns about lower lymphocyte levels in HIV with the once-daily oral drug islatravir in combination with doravirine changed the trajectory of clinical trial plans that are now back on track, according to investigators.

The nucleoside reverse transcriptase translocation inhibitor hit a roadblock in December 2021 when the U.S. Food and Drug Administration put a hold on investigational new drug applications for both the oral and implant formulations of islatravir after some patients in clinical trials showed decreases in total lymphocyte and CD4+ cell counts.

A phase 3, double-blind, randomized, controlled trial was underway at the time of once-daily islatravir (0.75 mg) in combination with 100 mg doravirine, compared with bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) as initial therapy for HIV infection in treatment-naïve individuals. Recruitment was stopped, 83 participants short of the planned 680, but the trial could continue the full 48 weeks.

Jürgen Rockstroh, MD, professor of medicine and head of the HIV Outpatient Clinic at the University of Bonn, Germany, presented the latest results from that trial of 597 patients at the International AIDS Society conference on HIV Science.

At week 48 after starting therapy, 88.9% of participants in the islatravir and doravirine arm and 88.3% of patients in the B/F/TAF arm achieved the primary outcome of HIV-1 RNA levels below 50 copies/mL.

One patient treated with islatravir and doravirine and four patients taking B/F/TAF experienced virologic failure.

Dr. Rockstroh told the conference the patient who developed viremia with the new islatravir combination had very high viral load at baseline but showed a rapid response to treatment, which reduced his viral load down to around 1,200 copies/mL by week 4.

However, by week 24, his islatravir concentration had reduced below detectable levels, suggesting a problem with adherence. His viral load increased again, and three treatment-resistant mutations were detected.

While both arms of the study showed a significant increase in CD4+ T cell counts, Dr. Rockstroh pointed out that some individuals in the islatravir and doravirine arm had a lower absolute increase in lymphocyte counts at week 48.

Overall, the mean change in CD4+ T cell counts was 182 cells/mL in the islatravir and doravirine group, compared with 234 cells/mL in the B/F/TAF group.

More patients in the islatravir combination arm discontinued treatment due to a decrease in CD4+ T cell or total lymphocyte counts – 5.4%, compared with 2% in the B/F/TAF arm, however.

“These changes in lymphocyte counts did not lead to any difference in the amount of infection-related adverse events, which happened in both arms in relatively comparable percentages,” Dr. Rockstroh said at the conference.
 

New lower dose

Because of persistent concerns about the impact on CD4+ T cells and total lymphocytes, Dr. Rockstroh said another phase 3 trial is now underway using a lower 0.25 mg dose of islatravir, again combined with 100 mg doravirine, in people who are treatment-naïve and virologically suppressed.

The study also examined the impact of both treatments on weight gain and found the mean change in weight was similar between both arms – 3.45 kg gain in those on islatravir with doravirine and 3.32 kg gain in those on B/F/TAF, which was not significantly different.

There are several important reasons it is a good idea to have more treatment options available for people with HIV, Dr. Rockstroh said in an interview.

With integrase inhibitors potentially interfering with metabolic health, weight gain, hypertension, insulin resistance, and possible diabetes, “I think it’s wise that we at least have alternative strategies,” he said.

James McMahon, MD, PhD, an infectious diseases physician and head of the Infectious Diseases Clinical Research Unit at the Alfred Hospital and Monash University in Melbourne, said there is always a need for new HIV treatments, particularly ones that are more powerful.

“Whenever you get a drug that’s potent at low dose, it means you can have smaller pills, [and] you can then consider giving more of it in long-acting formulations,” Dr. McMahon said.

He pointed out that the study did not show any signal of increased infections with the lower CD4+ T cell counts in the islatravir and doravirine arm, “but that difference is enough to raise that concern that it’s not ideal, and it should be moved forward with a lower dose, which is what they’ve done.”

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

Brisbane, Australia – Concerns about lower lymphocyte levels in HIV with the once-daily oral drug islatravir in combination with doravirine changed the trajectory of clinical trial plans that are now back on track, according to investigators.

The nucleoside reverse transcriptase translocation inhibitor hit a roadblock in December 2021 when the U.S. Food and Drug Administration put a hold on investigational new drug applications for both the oral and implant formulations of islatravir after some patients in clinical trials showed decreases in total lymphocyte and CD4+ cell counts.

A phase 3, double-blind, randomized, controlled trial was underway at the time of once-daily islatravir (0.75 mg) in combination with 100 mg doravirine, compared with bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) as initial therapy for HIV infection in treatment-naïve individuals. Recruitment was stopped, 83 participants short of the planned 680, but the trial could continue the full 48 weeks.

Jürgen Rockstroh, MD, professor of medicine and head of the HIV Outpatient Clinic at the University of Bonn, Germany, presented the latest results from that trial of 597 patients at the International AIDS Society conference on HIV Science.

At week 48 after starting therapy, 88.9% of participants in the islatravir and doravirine arm and 88.3% of patients in the B/F/TAF arm achieved the primary outcome of HIV-1 RNA levels below 50 copies/mL.

One patient treated with islatravir and doravirine and four patients taking B/F/TAF experienced virologic failure.

Dr. Rockstroh told the conference the patient who developed viremia with the new islatravir combination had very high viral load at baseline but showed a rapid response to treatment, which reduced his viral load down to around 1,200 copies/mL by week 4.

However, by week 24, his islatravir concentration had reduced below detectable levels, suggesting a problem with adherence. His viral load increased again, and three treatment-resistant mutations were detected.

While both arms of the study showed a significant increase in CD4+ T cell counts, Dr. Rockstroh pointed out that some individuals in the islatravir and doravirine arm had a lower absolute increase in lymphocyte counts at week 48.

Overall, the mean change in CD4+ T cell counts was 182 cells/mL in the islatravir and doravirine group, compared with 234 cells/mL in the B/F/TAF group.

More patients in the islatravir combination arm discontinued treatment due to a decrease in CD4+ T cell or total lymphocyte counts – 5.4%, compared with 2% in the B/F/TAF arm, however.

“These changes in lymphocyte counts did not lead to any difference in the amount of infection-related adverse events, which happened in both arms in relatively comparable percentages,” Dr. Rockstroh said at the conference.
 

New lower dose

Because of persistent concerns about the impact on CD4+ T cells and total lymphocytes, Dr. Rockstroh said another phase 3 trial is now underway using a lower 0.25 mg dose of islatravir, again combined with 100 mg doravirine, in people who are treatment-naïve and virologically suppressed.

The study also examined the impact of both treatments on weight gain and found the mean change in weight was similar between both arms – 3.45 kg gain in those on islatravir with doravirine and 3.32 kg gain in those on B/F/TAF, which was not significantly different.

There are several important reasons it is a good idea to have more treatment options available for people with HIV, Dr. Rockstroh said in an interview.

With integrase inhibitors potentially interfering with metabolic health, weight gain, hypertension, insulin resistance, and possible diabetes, “I think it’s wise that we at least have alternative strategies,” he said.

James McMahon, MD, PhD, an infectious diseases physician and head of the Infectious Diseases Clinical Research Unit at the Alfred Hospital and Monash University in Melbourne, said there is always a need for new HIV treatments, particularly ones that are more powerful.

“Whenever you get a drug that’s potent at low dose, it means you can have smaller pills, [and] you can then consider giving more of it in long-acting formulations,” Dr. McMahon said.

He pointed out that the study did not show any signal of increased infections with the lower CD4+ T cell counts in the islatravir and doravirine arm, “but that difference is enough to raise that concern that it’s not ideal, and it should be moved forward with a lower dose, which is what they’ve done.”

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

Clinics have been coming up with new ways to add injections to their offerings ever since a new long-acting formulation of cabotegravir has been available to treat people with HIV.

At the Whitman-Walker Health Center, Washington, community health workers see about 3,200 antiretroviral users a year. With long-acting injections now available, the clinic opted to integrate the new medications into its peer staff program.

“Our peer workers are very competent,” said Rupa Patel, MD, MPH, medical liason of the pre-exposure prophylaxis for HIV prevention program at Washington University at St. Louis.* “They do phlebotomy, they give you your meds. They’re your main doctor until you really need to see the doctor.”

In the peer staff program, workers are trained in a 4-month medical residency–style program that shows them how to test for HIV, inject long-acting formulations of new drugs, and conduct follow-up visits.

Presenting the new approach at the International AIDS Society Conference on HIV Science, Dr. Patel reported that 139 people have received long-acting injections at the clinic since the program launched with a total of 314 injections administered.

The training program includes lectures, mock injection, and client care sessions, observation and supervised administration, a written exam, and case review sessions.

Retention for the second injection was 95%, with 91% of injections given within the 14-day window. For the third injection, retention was 91%, with 63% given within the window.

The program reports a high level of client satisfaction with the peer-administered injections, which are also given in a room decorated with a beach theme and music to help calm people who might be nervous of receiving shots.

“Our retention is going to be the highest compared to other clinics because your peer, your friend, is reminding you and comforting you and telling you: ‘Don’t worry, I’m on the injection too,’ ” Dr. Patel said.

Andrew Grulich, MD, PhD, head of the HIV epidemiology and prevention program at the Kirby Institute, Sydney, pointed out there is tension between wanting to use long-acting injectables for people who are struggling with taking oral therapies daily and the need to ensure that they come back for their injections on time.

“I think it’s a potential way forward – we’re learning as we’re going with these new forms of therapy,” he said in an interview. “It is absolutely critical that people turn up on time for those injections, and if they don’t, resistance can be an issue.”

Presenting new data from another project at the HIV Clinic at San Francisco General Hospital, Monica Gandhi, MD, MPH, told the conference: “There are multiple reasons why it’s hard to take oral antiretrovirals every day.”

At the HIV Clinic in San Francisco General, people without homes, those with mental illness, and those using stimulants receive care.

The clinical trials for long-acting injectable antiretrovirals included only people who were virologically suppressed, which is also the Food and Drug Administration criteria for use. However, this clinic offered long-acting injections to patients with viremia because it was too difficult for them to take a daily pill.

In a comment, Dr. Gandhi, director of the University of California, San Francisco’s Center for AIDS Research, said: “We don’t call people hard to reach, we call them hardly reached because it’s not their fault.” There are just all of these issues that have made it harder for them to take medication consistently.

Dr. Gandhi reported that, of the 133 people being treated with long-acting injectable cabotegravir and rilpivirine at the clinic through this program, 57 had viremia at baseline.

However, only two of these patients experienced virologic failure while on the injectable antiretroviral program. The overall virologic failure rate was 1.5%, which was equivalent to that seen in clinical trials in virologically suppressed individuals.

The results presented at the conference and were also published in Annals of Internal Medicine.

The clinic found that 73% of people attended their injection appointments on time, and those who did not were followed up with telephone calls to ensure they received their injection within the 14-day window.

Dr. Gandhi said people were highly motivated to turn up for their injection appointments. “They are virologically suppressed, so it feels so amazing. They’re self-motivated for the first time to want to get an injection.”

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

*Correction, 8/4/23: An earlier version of this article misstated Dr. Patel's university affiliation.

Clinics have been coming up with new ways to add injections to their offerings ever since a new long-acting formulation of cabotegravir has been available to treat people with HIV.

At the Whitman-Walker Health Center, Washington, community health workers see about 3,200 antiretroviral users a year. With long-acting injections now available, the clinic opted to integrate the new medications into its peer staff program.

“Our peer workers are very competent,” said Rupa Patel, MD, MPH, medical liason of the pre-exposure prophylaxis for HIV prevention program at Washington University at St. Louis.* “They do phlebotomy, they give you your meds. They’re your main doctor until you really need to see the doctor.”

In the peer staff program, workers are trained in a 4-month medical residency–style program that shows them how to test for HIV, inject long-acting formulations of new drugs, and conduct follow-up visits.

Presenting the new approach at the International AIDS Society Conference on HIV Science, Dr. Patel reported that 139 people have received long-acting injections at the clinic since the program launched with a total of 314 injections administered.

The training program includes lectures, mock injection, and client care sessions, observation and supervised administration, a written exam, and case review sessions.

Retention for the second injection was 95%, with 91% of injections given within the 14-day window. For the third injection, retention was 91%, with 63% given within the window.

The program reports a high level of client satisfaction with the peer-administered injections, which are also given in a room decorated with a beach theme and music to help calm people who might be nervous of receiving shots.

“Our retention is going to be the highest compared to other clinics because your peer, your friend, is reminding you and comforting you and telling you: ‘Don’t worry, I’m on the injection too,’ ” Dr. Patel said.

Andrew Grulich, MD, PhD, head of the HIV epidemiology and prevention program at the Kirby Institute, Sydney, pointed out there is tension between wanting to use long-acting injectables for people who are struggling with taking oral therapies daily and the need to ensure that they come back for their injections on time.

“I think it’s a potential way forward – we’re learning as we’re going with these new forms of therapy,” he said in an interview. “It is absolutely critical that people turn up on time for those injections, and if they don’t, resistance can be an issue.”

Presenting new data from another project at the HIV Clinic at San Francisco General Hospital, Monica Gandhi, MD, MPH, told the conference: “There are multiple reasons why it’s hard to take oral antiretrovirals every day.”

At the HIV Clinic in San Francisco General, people without homes, those with mental illness, and those using stimulants receive care.

The clinical trials for long-acting injectable antiretrovirals included only people who were virologically suppressed, which is also the Food and Drug Administration criteria for use. However, this clinic offered long-acting injections to patients with viremia because it was too difficult for them to take a daily pill.

In a comment, Dr. Gandhi, director of the University of California, San Francisco’s Center for AIDS Research, said: “We don’t call people hard to reach, we call them hardly reached because it’s not their fault.” There are just all of these issues that have made it harder for them to take medication consistently.

Dr. Gandhi reported that, of the 133 people being treated with long-acting injectable cabotegravir and rilpivirine at the clinic through this program, 57 had viremia at baseline.

However, only two of these patients experienced virologic failure while on the injectable antiretroviral program. The overall virologic failure rate was 1.5%, which was equivalent to that seen in clinical trials in virologically suppressed individuals.

The results presented at the conference and were also published in Annals of Internal Medicine.

The clinic found that 73% of people attended their injection appointments on time, and those who did not were followed up with telephone calls to ensure they received their injection within the 14-day window.

Dr. Gandhi said people were highly motivated to turn up for their injection appointments. “They are virologically suppressed, so it feels so amazing. They’re self-motivated for the first time to want to get an injection.”

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

*Correction, 8/4/23: An earlier version of this article misstated Dr. Patel's university affiliation.

Clinics have been coming up with new ways to add injections to their offerings ever since a new long-acting formulation of cabotegravir has been available to treat people with HIV.

At the Whitman-Walker Health Center, Washington, community health workers see about 3,200 antiretroviral users a year. With long-acting injections now available, the clinic opted to integrate the new medications into its peer staff program.

“Our peer workers are very competent,” said Rupa Patel, MD, MPH, medical liason of the pre-exposure prophylaxis for HIV prevention program at Washington University at St. Louis.* “They do phlebotomy, they give you your meds. They’re your main doctor until you really need to see the doctor.”

In the peer staff program, workers are trained in a 4-month medical residency–style program that shows them how to test for HIV, inject long-acting formulations of new drugs, and conduct follow-up visits.

Presenting the new approach at the International AIDS Society Conference on HIV Science, Dr. Patel reported that 139 people have received long-acting injections at the clinic since the program launched with a total of 314 injections administered.

The training program includes lectures, mock injection, and client care sessions, observation and supervised administration, a written exam, and case review sessions.

Retention for the second injection was 95%, with 91% of injections given within the 14-day window. For the third injection, retention was 91%, with 63% given within the window.

The program reports a high level of client satisfaction with the peer-administered injections, which are also given in a room decorated with a beach theme and music to help calm people who might be nervous of receiving shots.

“Our retention is going to be the highest compared to other clinics because your peer, your friend, is reminding you and comforting you and telling you: ‘Don’t worry, I’m on the injection too,’ ” Dr. Patel said.

Andrew Grulich, MD, PhD, head of the HIV epidemiology and prevention program at the Kirby Institute, Sydney, pointed out there is tension between wanting to use long-acting injectables for people who are struggling with taking oral therapies daily and the need to ensure that they come back for their injections on time.

“I think it’s a potential way forward – we’re learning as we’re going with these new forms of therapy,” he said in an interview. “It is absolutely critical that people turn up on time for those injections, and if they don’t, resistance can be an issue.”

Presenting new data from another project at the HIV Clinic at San Francisco General Hospital, Monica Gandhi, MD, MPH, told the conference: “There are multiple reasons why it’s hard to take oral antiretrovirals every day.”

At the HIV Clinic in San Francisco General, people without homes, those with mental illness, and those using stimulants receive care.

The clinical trials for long-acting injectable antiretrovirals included only people who were virologically suppressed, which is also the Food and Drug Administration criteria for use. However, this clinic offered long-acting injections to patients with viremia because it was too difficult for them to take a daily pill.

In a comment, Dr. Gandhi, director of the University of California, San Francisco’s Center for AIDS Research, said: “We don’t call people hard to reach, we call them hardly reached because it’s not their fault.” There are just all of these issues that have made it harder for them to take medication consistently.

Dr. Gandhi reported that, of the 133 people being treated with long-acting injectable cabotegravir and rilpivirine at the clinic through this program, 57 had viremia at baseline.

However, only two of these patients experienced virologic failure while on the injectable antiretroviral program. The overall virologic failure rate was 1.5%, which was equivalent to that seen in clinical trials in virologically suppressed individuals.

The results presented at the conference and were also published in Annals of Internal Medicine.

The clinic found that 73% of people attended their injection appointments on time, and those who did not were followed up with telephone calls to ensure they received their injection within the 14-day window.

Dr. Gandhi said people were highly motivated to turn up for their injection appointments. “They are virologically suppressed, so it feels so amazing. They’re self-motivated for the first time to want to get an injection.”

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

*Correction, 8/4/23: An earlier version of this article misstated Dr. Patel's university affiliation.

BRISBANE, AUSTRALIA – The year was 1987 and the Grim Reaper (a personification of death), holding a large scythe, rolled a 10-pin bowling ball through a dark, foggy place. In the advertisement on television, the cloaked skeleton aimed the bowling ball at the other end of a lane where a group of people stood in place of pins.

Who would fall next?

In the 1980s, cases of HIV were rising in the community and people in Australia and elsewhere were dying of AIDS. The Australian government opted to use mainstream media to deliver a blunt message through advertising to raise awareness about the health risk and how to manage HIV in the community.

But the campaign also contributed to stigma for those living with the disease and especially those in the gay community who felt ostracized by rising public concern.

In the inner city of Sydney, a few thousand people died of AIDS, Andrew Grulich, MD, PhD, from the Kirby Institute at the University of New South Wales, Sydney, and involved in tracking cases, said in an interview. “Sydney was devastated by AIDS, it was truly devastated.”

HIV and AIDS quickly became an even more severe problem for several countries around Australia in Thailand, Papua New Guinea, and beyond. After HIV was first reported in Thailand in 1984, the region had the highest prevalence of HIV in Southeast Asia. Through the 1990s in Papua New Guinea, HIV prevalence rose steeply as well.

By 2010, the Joint United Nations Programme on HIV/AIDS (UNAIDS) set a target of a 90% reduction in HIV incidence, a 90% reduction in AIDS deaths by 2030, and 95% of people living with HIV and AIDS being aware of their status, on treatment, and having an undetectable viral load.

Since then, significant progress has been made globally with 86% of people knowing their HIV status. However, new infections persist at a rate that has not dropped as fast as possible.
 

New infections

According to the latest UNAIDS report, regions of North America and western and central Europe showed a 23% decline in new infections from 2010 to 2022, below the target 90% reduction.

Some regions of the United States have seen significant declines in new HIV infections. San Francisco has a 67% drop in new diagnoses. And now, along with the District of Columbia, the four states with the highest HIV rates are New York, Maryland, Georgia, and Florida.

Several countries in eastern and southern Africa are close to achieving their target HIV reduction of 90%.

Mitchell Warren, executive director of AVAC for global health advocacy, access, and equity, said that many of the low- and middle-income countries that are on track to achieve targets are able to do so because of support from the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis, and Malaria.

“That foreign development assistance is transforming the AIDS response in a number of African countries, and yet at home, in various states and municipalities, not only are we not reaching that effort, we don’t even use those targets,” Mr. Warren pointed out.

“We might see municipalities that are performing well, but at a national level it’s frankly a disgrace by comparison, because we know what’s possible,” Mr. Warren said.
 

Lowering cases

Today, in the inner city of Sydney, new HIV diagnoses have plummeted by 88%, which puts the area on track to achieve the 90% UNAIDS target ahead of schedule.

Dr. Grulich and his team at the Kirby Institute are tracking new diagnoses by postal code and reported their encouraging findings here this week at the International AIDS Society Conference on HIV Science.

“This 88% decline is happening in an area where, in the ’80s and ’90s, a few thousand people died of AIDS,” Dr. Grulich told this news organization. “It feels close to miraculous.”

Dr. Grulich attributes some of the success to long-term government leadership that for the most part has been apolitical. HIV has been perceived by the public as an important health issue to be addressed. “We’ve never had a political contest over it,” he added. “We have politicians who are committed to evidence-based policy.”

In inner city Sydney, HIV prevention campaigns are a visible part of community life, Dr. Grulich explained. At public events, it is discussed; at bus stops, posters are on display; and passing trains have messages plastered to the side of them.

That community effort has consistently received government funding for years – albeit linked to key performance indicators – but it has enabled a high level of communication among government, community, clinicians, and researchers.

Another advantage is Australia’s universal health coverage, said Sharon Lewin, PhD, president of the International AIDS Society and director of the Peter Doherty Institute for Infection and Immunity at the University of Melbourne. “One very clear difference for Australia is a health system that provides free medication and free prevention,” she said. “You can’t underestimate the impact that has on public health.”

Globally, significant progress has been made toward the UN’s 95-95-95 targets, with 86% of people with HIV now knowing their status, 88% of those being on treatment, and 93% of those having an undetectable viral load, “for a total of 75% of all people living with HIV worldwide with undetectable viral load,” Dr. Grulich pointed out.

But Dr. Lewin cautioned that now is not the time to take our eye off the ball, especially with respect to the 39 million or so people living with HIV globally, all of whom need lifelong treatment and care to manage their disease. “We also need to be aware that if we relax the investment, and people stop their treatment, transmission occurs again,” Dr. Lewin warned. “Despite the great news of potentially getting close to eliminating HIV transmission in Australia, HIV is far from over.”

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

BRISBANE, AUSTRALIA – The year was 1987 and the Grim Reaper (a personification of death), holding a large scythe, rolled a 10-pin bowling ball through a dark, foggy place. In the advertisement on television, the cloaked skeleton aimed the bowling ball at the other end of a lane where a group of people stood in place of pins.

Who would fall next?

In the 1980s, cases of HIV were rising in the community and people in Australia and elsewhere were dying of AIDS. The Australian government opted to use mainstream media to deliver a blunt message through advertising to raise awareness about the health risk and how to manage HIV in the community.

But the campaign also contributed to stigma for those living with the disease and especially those in the gay community who felt ostracized by rising public concern.

In the inner city of Sydney, a few thousand people died of AIDS, Andrew Grulich, MD, PhD, from the Kirby Institute at the University of New South Wales, Sydney, and involved in tracking cases, said in an interview. “Sydney was devastated by AIDS, it was truly devastated.”

HIV and AIDS quickly became an even more severe problem for several countries around Australia in Thailand, Papua New Guinea, and beyond. After HIV was first reported in Thailand in 1984, the region had the highest prevalence of HIV in Southeast Asia. Through the 1990s in Papua New Guinea, HIV prevalence rose steeply as well.

By 2010, the Joint United Nations Programme on HIV/AIDS (UNAIDS) set a target of a 90% reduction in HIV incidence, a 90% reduction in AIDS deaths by 2030, and 95% of people living with HIV and AIDS being aware of their status, on treatment, and having an undetectable viral load.

Since then, significant progress has been made globally with 86% of people knowing their HIV status. However, new infections persist at a rate that has not dropped as fast as possible.
 

New infections

According to the latest UNAIDS report, regions of North America and western and central Europe showed a 23% decline in new infections from 2010 to 2022, below the target 90% reduction.

Some regions of the United States have seen significant declines in new HIV infections. San Francisco has a 67% drop in new diagnoses. And now, along with the District of Columbia, the four states with the highest HIV rates are New York, Maryland, Georgia, and Florida.

Several countries in eastern and southern Africa are close to achieving their target HIV reduction of 90%.

Mitchell Warren, executive director of AVAC for global health advocacy, access, and equity, said that many of the low- and middle-income countries that are on track to achieve targets are able to do so because of support from the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis, and Malaria.

“That foreign development assistance is transforming the AIDS response in a number of African countries, and yet at home, in various states and municipalities, not only are we not reaching that effort, we don’t even use those targets,” Mr. Warren pointed out.

“We might see municipalities that are performing well, but at a national level it’s frankly a disgrace by comparison, because we know what’s possible,” Mr. Warren said.
 

Lowering cases

Today, in the inner city of Sydney, new HIV diagnoses have plummeted by 88%, which puts the area on track to achieve the 90% UNAIDS target ahead of schedule.

Dr. Grulich and his team at the Kirby Institute are tracking new diagnoses by postal code and reported their encouraging findings here this week at the International AIDS Society Conference on HIV Science.

“This 88% decline is happening in an area where, in the ’80s and ’90s, a few thousand people died of AIDS,” Dr. Grulich told this news organization. “It feels close to miraculous.”

Dr. Grulich attributes some of the success to long-term government leadership that for the most part has been apolitical. HIV has been perceived by the public as an important health issue to be addressed. “We’ve never had a political contest over it,” he added. “We have politicians who are committed to evidence-based policy.”

In inner city Sydney, HIV prevention campaigns are a visible part of community life, Dr. Grulich explained. At public events, it is discussed; at bus stops, posters are on display; and passing trains have messages plastered to the side of them.

That community effort has consistently received government funding for years – albeit linked to key performance indicators – but it has enabled a high level of communication among government, community, clinicians, and researchers.

Another advantage is Australia’s universal health coverage, said Sharon Lewin, PhD, president of the International AIDS Society and director of the Peter Doherty Institute for Infection and Immunity at the University of Melbourne. “One very clear difference for Australia is a health system that provides free medication and free prevention,” she said. “You can’t underestimate the impact that has on public health.”

Globally, significant progress has been made toward the UN’s 95-95-95 targets, with 86% of people with HIV now knowing their status, 88% of those being on treatment, and 93% of those having an undetectable viral load, “for a total of 75% of all people living with HIV worldwide with undetectable viral load,” Dr. Grulich pointed out.

But Dr. Lewin cautioned that now is not the time to take our eye off the ball, especially with respect to the 39 million or so people living with HIV globally, all of whom need lifelong treatment and care to manage their disease. “We also need to be aware that if we relax the investment, and people stop their treatment, transmission occurs again,” Dr. Lewin warned. “Despite the great news of potentially getting close to eliminating HIV transmission in Australia, HIV is far from over.”

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

BRISBANE, AUSTRALIA – The year was 1987 and the Grim Reaper (a personification of death), holding a large scythe, rolled a 10-pin bowling ball through a dark, foggy place. In the advertisement on television, the cloaked skeleton aimed the bowling ball at the other end of a lane where a group of people stood in place of pins.

Who would fall next?

In the 1980s, cases of HIV were rising in the community and people in Australia and elsewhere were dying of AIDS. The Australian government opted to use mainstream media to deliver a blunt message through advertising to raise awareness about the health risk and how to manage HIV in the community.

But the campaign also contributed to stigma for those living with the disease and especially those in the gay community who felt ostracized by rising public concern.

In the inner city of Sydney, a few thousand people died of AIDS, Andrew Grulich, MD, PhD, from the Kirby Institute at the University of New South Wales, Sydney, and involved in tracking cases, said in an interview. “Sydney was devastated by AIDS, it was truly devastated.”

HIV and AIDS quickly became an even more severe problem for several countries around Australia in Thailand, Papua New Guinea, and beyond. After HIV was first reported in Thailand in 1984, the region had the highest prevalence of HIV in Southeast Asia. Through the 1990s in Papua New Guinea, HIV prevalence rose steeply as well.

By 2010, the Joint United Nations Programme on HIV/AIDS (UNAIDS) set a target of a 90% reduction in HIV incidence, a 90% reduction in AIDS deaths by 2030, and 95% of people living with HIV and AIDS being aware of their status, on treatment, and having an undetectable viral load.

Since then, significant progress has been made globally with 86% of people knowing their HIV status. However, new infections persist at a rate that has not dropped as fast as possible.
 

New infections

According to the latest UNAIDS report, regions of North America and western and central Europe showed a 23% decline in new infections from 2010 to 2022, below the target 90% reduction.

Some regions of the United States have seen significant declines in new HIV infections. San Francisco has a 67% drop in new diagnoses. And now, along with the District of Columbia, the four states with the highest HIV rates are New York, Maryland, Georgia, and Florida.

Several countries in eastern and southern Africa are close to achieving their target HIV reduction of 90%.

Mitchell Warren, executive director of AVAC for global health advocacy, access, and equity, said that many of the low- and middle-income countries that are on track to achieve targets are able to do so because of support from the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis, and Malaria.

“That foreign development assistance is transforming the AIDS response in a number of African countries, and yet at home, in various states and municipalities, not only are we not reaching that effort, we don’t even use those targets,” Mr. Warren pointed out.

“We might see municipalities that are performing well, but at a national level it’s frankly a disgrace by comparison, because we know what’s possible,” Mr. Warren said.
 

Lowering cases

Today, in the inner city of Sydney, new HIV diagnoses have plummeted by 88%, which puts the area on track to achieve the 90% UNAIDS target ahead of schedule.

Dr. Grulich and his team at the Kirby Institute are tracking new diagnoses by postal code and reported their encouraging findings here this week at the International AIDS Society Conference on HIV Science.

“This 88% decline is happening in an area where, in the ’80s and ’90s, a few thousand people died of AIDS,” Dr. Grulich told this news organization. “It feels close to miraculous.”

Dr. Grulich attributes some of the success to long-term government leadership that for the most part has been apolitical. HIV has been perceived by the public as an important health issue to be addressed. “We’ve never had a political contest over it,” he added. “We have politicians who are committed to evidence-based policy.”

In inner city Sydney, HIV prevention campaigns are a visible part of community life, Dr. Grulich explained. At public events, it is discussed; at bus stops, posters are on display; and passing trains have messages plastered to the side of them.

That community effort has consistently received government funding for years – albeit linked to key performance indicators – but it has enabled a high level of communication among government, community, clinicians, and researchers.

Another advantage is Australia’s universal health coverage, said Sharon Lewin, PhD, president of the International AIDS Society and director of the Peter Doherty Institute for Infection and Immunity at the University of Melbourne. “One very clear difference for Australia is a health system that provides free medication and free prevention,” she said. “You can’t underestimate the impact that has on public health.”

Globally, significant progress has been made toward the UN’s 95-95-95 targets, with 86% of people with HIV now knowing their status, 88% of those being on treatment, and 93% of those having an undetectable viral load, “for a total of 75% of all people living with HIV worldwide with undetectable viral load,” Dr. Grulich pointed out.

But Dr. Lewin cautioned that now is not the time to take our eye off the ball, especially with respect to the 39 million or so people living with HIV globally, all of whom need lifelong treatment and care to manage their disease. “We also need to be aware that if we relax the investment, and people stop their treatment, transmission occurs again,” Dr. Lewin warned. “Despite the great news of potentially getting close to eliminating HIV transmission in Australia, HIV is far from over.”

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

BRISBANE, AUSTRALIA – Statins should be considered for primary prevention in people living with HIV who are at low to moderate risk of cardiovascular disease, according to final data from the REPRIEVE trial that show pitavastatin therapy is associated with a significantly lower risk of cardiovascular events than placebo.

“There was a significant 35% lower risk of major adverse cardiovascular events after a median follow-up of 5.1 years “ said Steven Grinspoon, MD, from Massachusetts General Hospital and Harvard Medical School in Boston, who presented the final analysis of data from the REPRIEVE trial at the International AIDS Society Conference on HIV Science.

The results were simultaneously published in the New England Journal of Medicine. The primary endpoint of major adverse cardiovascular events included a composite of outcomes that included cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina, and transient ischemic attack among those treated with pitavastatin, compared with placebo (95% confidence interval, 0.48-0.90; P = .002).

The REPRIEVE trial was halted earlier this year for efficacy after an interim analysis pointed to a significantly lower rate of cardiovascular events in the treatment group.

The international double-blind, placebo-controlled trial randomly assigned 7,769 people with HIV infection, who were at low to moderate risk of cardiovascular disease, to either 4 mg daily of pitavastatin calcium or placebo.

The secondary outcome – a composite of major cardiovascular events and all-cause mortality – also showed a significant 21% reduction in risk with pitavastatin treatment, compared with placebo (95% CI, 0.65-0.96).
 

Cardiovascular events in HIV

HIV infection is an independent risk factor for cardiovascular disease, Dr. Grinspoon pointed out, and those living with HIV have about double the risk of myocardial infarction and stroke, compared with the general population.

“There’s an unmet need for people living with HIV who have low to moderate traditional risk, for whom HIV is even considered a risk equivalent but for whom no primary prevention strategy has been tested in a large trial,” Dr. Grinspoon said during an interview.

Those enrolled in the study had a 10-year Atherosclerotic Cardiovascular Disease risk score ranging from 2.1% to 7%, with a median of 4.5%. While LDL cholesterol levels at baseline ranged from 87 to 128 mg/dL, the study showed a similar reduction in cardiovascular risk regardless of LDL.

“These are types of people who, if they came to the doctor’s office right now before REPRIEVE, they would largely be told your risk score is not really making you eligible for a statin,” Dr. Grinspoon said.

He explained that what is most interesting about the reduction in risk is that it was nearly twice what would be expected with LDL lowering, based on what has previously been seen in statin trials in non–HIV-positive populations.

“I think the data are suggesting that it’s certainly in part due to the reduction in LDL – that is very important – but it’s also due to other factors beyond changes in LDL,” Dr. Grinspoon said. He speculated that the statin could be affecting anti-inflammatory and immune pathways, and that this could account for some of the reduction in cardiovascular risk, but “those data are cooking, and they’re being analyzed as we speak.”

In a substudy analysis of REPRIEVE, Markella Zanni, MD, associate professor of medicine at Harvard Medical School and Massachusetts General Hospital, focused on the women in the clinical trial.
 

Women’s risk

In REPRIEVE, 31.1% of the study population were women. Dr. Zanni and her team investigated whether there are differences in the way HIV affects the risk of developing atherosclerotic cardiovascular disease in women, compared with men.

They found that women have both higher levels of inflammatory markers, such as interleukin-6, C-reactive protein, and D-dimer, but a lower prevalence of coronary artery plaques than men.

“This finding represents an interesting paradox given that high levels of select inflammatory markers have been associated with coronary artery plaque, both among women living with HIV and among men living with HIV,” Dr. Zanni explained.

She says the researchers were hoping to further explore whether inflammation is fueling the increased risk for atherosclerotic disease, and particularly the higher risk evident in women living with HIV, compared with men.

“Women living with HIV should discuss with their treating clinicians heart risks and possible prevention strategies, including statin therapy coupled with healthy lifestyle changes addressing modifiable, traditional metabolic risk factors” she said.
 

Time for primary prevention?

All patients in the study were on antiretroviral therapy and investigators report that pitavastatin does not interact with these medications. The median CD4 cell count was 621 cells/mm³, and 87.5% of participants had an HIV viral load below the lower limit of quantification.

Participants were enrolled from 12 countries including the United States, Spain, Brazil, South Africa, and Thailand, and around two-thirds were non-White. Individuals of South Asian ethnicity showed the biggest reduction in cardiovascular risk with pitavastatin treatment.

There was a 74% higher rate of muscle pain and weakness in the pitavastatin group – affecting 91 people in the treatment arm and 53 in the placebo arm – but the majority were low grade. The rate of rhabdomyolysis of grade 3 or above was lower in the statin group, with three cases, compared with four cases in the placebo group.

Commenting on the findings, Laura Waters, MD, a genitourinary and HIV medicine consultant at Central and North West London NHS Foundation Trust’s Mortimer Market Centre, said that, while HIV infection was considered a risk factor for cardiovascular disease, risk calculators don’t specifically adjust for HIV infection.

“Now that we’ve got effective HIV drugs and people can enjoy normal life expectancy, cardiovascular disease is a particular issue for people with HIV,” she said.

Dr. Waters, who was not involved with the study, suggested that people living with HIV should discuss the use of statins with their doctor, but she acknowledged there are some barriers to treatment in people living with HIV. “It’s another pill, and when it’s a borderline [decision] it is easy to say, ‘I have to think about it,’ ” she said, with the result that statin treatment is often deferred.

The REPRIEVE study was supported by grants from the National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare. Dr. Grinspoon declared institutional grants from National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare and consultancies unrelated to the study. Dr. Zanni reports no relevant financial relationships.

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

BRISBANE, AUSTRALIA – Statins should be considered for primary prevention in people living with HIV who are at low to moderate risk of cardiovascular disease, according to final data from the REPRIEVE trial that show pitavastatin therapy is associated with a significantly lower risk of cardiovascular events than placebo.

“There was a significant 35% lower risk of major adverse cardiovascular events after a median follow-up of 5.1 years “ said Steven Grinspoon, MD, from Massachusetts General Hospital and Harvard Medical School in Boston, who presented the final analysis of data from the REPRIEVE trial at the International AIDS Society Conference on HIV Science.

The results were simultaneously published in the New England Journal of Medicine. The primary endpoint of major adverse cardiovascular events included a composite of outcomes that included cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina, and transient ischemic attack among those treated with pitavastatin, compared with placebo (95% confidence interval, 0.48-0.90; P = .002).

The REPRIEVE trial was halted earlier this year for efficacy after an interim analysis pointed to a significantly lower rate of cardiovascular events in the treatment group.

The international double-blind, placebo-controlled trial randomly assigned 7,769 people with HIV infection, who were at low to moderate risk of cardiovascular disease, to either 4 mg daily of pitavastatin calcium or placebo.

The secondary outcome – a composite of major cardiovascular events and all-cause mortality – also showed a significant 21% reduction in risk with pitavastatin treatment, compared with placebo (95% CI, 0.65-0.96).
 

Cardiovascular events in HIV

HIV infection is an independent risk factor for cardiovascular disease, Dr. Grinspoon pointed out, and those living with HIV have about double the risk of myocardial infarction and stroke, compared with the general population.

“There’s an unmet need for people living with HIV who have low to moderate traditional risk, for whom HIV is even considered a risk equivalent but for whom no primary prevention strategy has been tested in a large trial,” Dr. Grinspoon said during an interview.

Those enrolled in the study had a 10-year Atherosclerotic Cardiovascular Disease risk score ranging from 2.1% to 7%, with a median of 4.5%. While LDL cholesterol levels at baseline ranged from 87 to 128 mg/dL, the study showed a similar reduction in cardiovascular risk regardless of LDL.

“These are types of people who, if they came to the doctor’s office right now before REPRIEVE, they would largely be told your risk score is not really making you eligible for a statin,” Dr. Grinspoon said.

He explained that what is most interesting about the reduction in risk is that it was nearly twice what would be expected with LDL lowering, based on what has previously been seen in statin trials in non–HIV-positive populations.

“I think the data are suggesting that it’s certainly in part due to the reduction in LDL – that is very important – but it’s also due to other factors beyond changes in LDL,” Dr. Grinspoon said. He speculated that the statin could be affecting anti-inflammatory and immune pathways, and that this could account for some of the reduction in cardiovascular risk, but “those data are cooking, and they’re being analyzed as we speak.”

In a substudy analysis of REPRIEVE, Markella Zanni, MD, associate professor of medicine at Harvard Medical School and Massachusetts General Hospital, focused on the women in the clinical trial.
 

Women’s risk

In REPRIEVE, 31.1% of the study population were women. Dr. Zanni and her team investigated whether there are differences in the way HIV affects the risk of developing atherosclerotic cardiovascular disease in women, compared with men.

They found that women have both higher levels of inflammatory markers, such as interleukin-6, C-reactive protein, and D-dimer, but a lower prevalence of coronary artery plaques than men.

“This finding represents an interesting paradox given that high levels of select inflammatory markers have been associated with coronary artery plaque, both among women living with HIV and among men living with HIV,” Dr. Zanni explained.

She says the researchers were hoping to further explore whether inflammation is fueling the increased risk for atherosclerotic disease, and particularly the higher risk evident in women living with HIV, compared with men.

“Women living with HIV should discuss with their treating clinicians heart risks and possible prevention strategies, including statin therapy coupled with healthy lifestyle changes addressing modifiable, traditional metabolic risk factors” she said.
 

Time for primary prevention?

All patients in the study were on antiretroviral therapy and investigators report that pitavastatin does not interact with these medications. The median CD4 cell count was 621 cells/mm³, and 87.5% of participants had an HIV viral load below the lower limit of quantification.

Participants were enrolled from 12 countries including the United States, Spain, Brazil, South Africa, and Thailand, and around two-thirds were non-White. Individuals of South Asian ethnicity showed the biggest reduction in cardiovascular risk with pitavastatin treatment.

There was a 74% higher rate of muscle pain and weakness in the pitavastatin group – affecting 91 people in the treatment arm and 53 in the placebo arm – but the majority were low grade. The rate of rhabdomyolysis of grade 3 or above was lower in the statin group, with three cases, compared with four cases in the placebo group.

Commenting on the findings, Laura Waters, MD, a genitourinary and HIV medicine consultant at Central and North West London NHS Foundation Trust’s Mortimer Market Centre, said that, while HIV infection was considered a risk factor for cardiovascular disease, risk calculators don’t specifically adjust for HIV infection.

“Now that we’ve got effective HIV drugs and people can enjoy normal life expectancy, cardiovascular disease is a particular issue for people with HIV,” she said.

Dr. Waters, who was not involved with the study, suggested that people living with HIV should discuss the use of statins with their doctor, but she acknowledged there are some barriers to treatment in people living with HIV. “It’s another pill, and when it’s a borderline [decision] it is easy to say, ‘I have to think about it,’ ” she said, with the result that statin treatment is often deferred.

The REPRIEVE study was supported by grants from the National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare. Dr. Grinspoon declared institutional grants from National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare and consultancies unrelated to the study. Dr. Zanni reports no relevant financial relationships.

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

BRISBANE, AUSTRALIA – Statins should be considered for primary prevention in people living with HIV who are at low to moderate risk of cardiovascular disease, according to final data from the REPRIEVE trial that show pitavastatin therapy is associated with a significantly lower risk of cardiovascular events than placebo.

“There was a significant 35% lower risk of major adverse cardiovascular events after a median follow-up of 5.1 years “ said Steven Grinspoon, MD, from Massachusetts General Hospital and Harvard Medical School in Boston, who presented the final analysis of data from the REPRIEVE trial at the International AIDS Society Conference on HIV Science.

The results were simultaneously published in the New England Journal of Medicine. The primary endpoint of major adverse cardiovascular events included a composite of outcomes that included cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina, and transient ischemic attack among those treated with pitavastatin, compared with placebo (95% confidence interval, 0.48-0.90; P = .002).

The REPRIEVE trial was halted earlier this year for efficacy after an interim analysis pointed to a significantly lower rate of cardiovascular events in the treatment group.

The international double-blind, placebo-controlled trial randomly assigned 7,769 people with HIV infection, who were at low to moderate risk of cardiovascular disease, to either 4 mg daily of pitavastatin calcium or placebo.

The secondary outcome – a composite of major cardiovascular events and all-cause mortality – also showed a significant 21% reduction in risk with pitavastatin treatment, compared with placebo (95% CI, 0.65-0.96).
 

Cardiovascular events in HIV

HIV infection is an independent risk factor for cardiovascular disease, Dr. Grinspoon pointed out, and those living with HIV have about double the risk of myocardial infarction and stroke, compared with the general population.

“There’s an unmet need for people living with HIV who have low to moderate traditional risk, for whom HIV is even considered a risk equivalent but for whom no primary prevention strategy has been tested in a large trial,” Dr. Grinspoon said during an interview.

Those enrolled in the study had a 10-year Atherosclerotic Cardiovascular Disease risk score ranging from 2.1% to 7%, with a median of 4.5%. While LDL cholesterol levels at baseline ranged from 87 to 128 mg/dL, the study showed a similar reduction in cardiovascular risk regardless of LDL.

“These are types of people who, if they came to the doctor’s office right now before REPRIEVE, they would largely be told your risk score is not really making you eligible for a statin,” Dr. Grinspoon said.

He explained that what is most interesting about the reduction in risk is that it was nearly twice what would be expected with LDL lowering, based on what has previously been seen in statin trials in non–HIV-positive populations.

“I think the data are suggesting that it’s certainly in part due to the reduction in LDL – that is very important – but it’s also due to other factors beyond changes in LDL,” Dr. Grinspoon said. He speculated that the statin could be affecting anti-inflammatory and immune pathways, and that this could account for some of the reduction in cardiovascular risk, but “those data are cooking, and they’re being analyzed as we speak.”

In a substudy analysis of REPRIEVE, Markella Zanni, MD, associate professor of medicine at Harvard Medical School and Massachusetts General Hospital, focused on the women in the clinical trial.
 

Women’s risk

In REPRIEVE, 31.1% of the study population were women. Dr. Zanni and her team investigated whether there are differences in the way HIV affects the risk of developing atherosclerotic cardiovascular disease in women, compared with men.

They found that women have both higher levels of inflammatory markers, such as interleukin-6, C-reactive protein, and D-dimer, but a lower prevalence of coronary artery plaques than men.

“This finding represents an interesting paradox given that high levels of select inflammatory markers have been associated with coronary artery plaque, both among women living with HIV and among men living with HIV,” Dr. Zanni explained.

She says the researchers were hoping to further explore whether inflammation is fueling the increased risk for atherosclerotic disease, and particularly the higher risk evident in women living with HIV, compared with men.

“Women living with HIV should discuss with their treating clinicians heart risks and possible prevention strategies, including statin therapy coupled with healthy lifestyle changes addressing modifiable, traditional metabolic risk factors” she said.
 

Time for primary prevention?

All patients in the study were on antiretroviral therapy and investigators report that pitavastatin does not interact with these medications. The median CD4 cell count was 621 cells/mm³, and 87.5% of participants had an HIV viral load below the lower limit of quantification.

Participants were enrolled from 12 countries including the United States, Spain, Brazil, South Africa, and Thailand, and around two-thirds were non-White. Individuals of South Asian ethnicity showed the biggest reduction in cardiovascular risk with pitavastatin treatment.

There was a 74% higher rate of muscle pain and weakness in the pitavastatin group – affecting 91 people in the treatment arm and 53 in the placebo arm – but the majority were low grade. The rate of rhabdomyolysis of grade 3 or above was lower in the statin group, with three cases, compared with four cases in the placebo group.

Commenting on the findings, Laura Waters, MD, a genitourinary and HIV medicine consultant at Central and North West London NHS Foundation Trust’s Mortimer Market Centre, said that, while HIV infection was considered a risk factor for cardiovascular disease, risk calculators don’t specifically adjust for HIV infection.

“Now that we’ve got effective HIV drugs and people can enjoy normal life expectancy, cardiovascular disease is a particular issue for people with HIV,” she said.

Dr. Waters, who was not involved with the study, suggested that people living with HIV should discuss the use of statins with their doctor, but she acknowledged there are some barriers to treatment in people living with HIV. “It’s another pill, and when it’s a borderline [decision] it is easy to say, ‘I have to think about it,’ ” she said, with the result that statin treatment is often deferred.

The REPRIEVE study was supported by grants from the National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare. Dr. Grinspoon declared institutional grants from National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare and consultancies unrelated to the study. Dr. Zanni reports no relevant financial relationships.

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

SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.

Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.

“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.

163867_Merrill_Joan_web.PNG

The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”

Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.

Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.

For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.

This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.

“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”

This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.

“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.

Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.

The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.

The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.

Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.

Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.

Furie_Richard_A_NY_web.jpg

Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.

But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.

If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.

“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”

Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.

SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.

Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.

“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.

163867_Merrill_Joan_web.PNG

The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”

Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.

Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.

For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.

This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.

“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”

This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.

“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.

Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.

The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.

The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.

Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.

Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.

Furie_Richard_A_NY_web.jpg

Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.

But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.

If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.

“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”

Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.

SEOUL, SOUTH KOREA – A major challenge for clinical trials in systemic lupus erythematosus (SLE) is how to get the placebo response rate down low enough that the effectiveness of a drug can actually be seen. Better patient selection may be the key.

Speaking at an international congress on SLE, Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, presented on how the heterogeneity of lupus is contributing to the ongoing failure of so many potential therapies in clinical trials.

“It’s a miracle that any drug has been successful in clinical trials,” she told the conference, comparing the few drugs approved for the treatment of lupus with the much larger numbers of approved, targeted biologics that are available for rheumatoid arthritis.

163867_Merrill_Joan_web.PNG

The problem is that placebo response rates in clinical trials for lupus are high – well over 40% – Dr. Merrill said, and trials aren’t showing a big difference in response rates between the treatment and placebo arms. “If the placebo response is 40%, wouldn’t an effective drug help 80%?” she said. “If it also affects only 40%, does that mean it’s a failed drug?”

Dr. Merrill suggested that better patient selection could be key to achieving lower placebo response rates, which could in turn reveal if and in whom a drug might be effective. “If we could get the placebo response rate down, at least we’d be able to see a little bit better whether the drug is effective, even if it only could work in 50% of the patients,” she said.

Data from research done by the Oklahoma Medical Research Foundation suggested that patients with SLE could be loosely categorized into seven different clusters based on patterns of gene expression in areas such as interferon expression and inflammation pathways.

For example, two of those clusters represented patients with high levels of expression for both interferons and inflammation. “Maybe those are the patients who’d want to be put in a trial for interferon inhibition,” Dr. Merrill said.

This was demonstrated in a trial of type 1 interferon inhibitor anifrolumab (Saphnelo), where patients were sorted into groups according to their level of interferon expression – either high or low – based on expression of certain interferon genes. This revealed that patients in the interferon-high group had a much higher treatment effect than patients in the interferon-low group. But the difference lay in the placebo response.

“The efficacy rate was not that different between the interferon-high and the interferon-low patients,” Dr. Merrill said. “The difference was in the placebo response rate – what they had managed to find was a great marker for sicker patients.”

This phenomenon is not limited to interferon-targeted therapies. Dr. Merrill cited another literature review which looked at subset studies within clinical trials that had delivered disappointing results. This showed consistently that patients who were considered more unwell, by virtue of higher SLE Disease Activity Index (SLEDAI) scores, for example, were more likely to show an effect of treatment.

“You begin to see bigger differences between treatment and placebo because the treatment rate might go up, but mostly because the placebo rate goes down,” she said.

Another issue that could be affecting both placebo and treatment response rates is background medication. “Subset analysis of people on less background drugs was showing lower placebo response rates and better differences between treatments and placebo,” Dr. Merrill said. For example, a recent phase 2 study of anifrolumab took the strategy of actively pursuing tapering of glucocorticoids in patients where that could be done safely. That achieved a lowering of the placebo response rate to the point where a greater difference could be seen between the placebo response and the treatment response rates.

The challenge for clinical trials is therefore to identify which patients to include. “If we could figure out which patients would be the most appropriate [to enroll to fit a particular drug’s mechanism of action], then we could really get ahead of the game,” she said.

The unique problem for lupus clinic trials is the heterogeneity of lupus as a disease, Dr. Merrill said in an interview. “We’re going to have to find combinations of treatments that fit right for each patient, and they won’t necessarily be one size fits all,” she said.

Dr. Merrill said that subset analyses at the phase 2 stage could help identify the patients who responded better to the treatment and could therefore be targeted in phase 3 trials. “Once you take that hypothesis, and if you can establish and validate it in phase 3, now you’ve got yourself a biomarker,” she said.

Richard A. Furie, MD, chief of the division of rheumatology at Northwell Health in New York, agreed that the high placebo response rate was a particular nemesis for researchers involved in lupus clinical trials.

Furie_Richard_A_NY_web.jpg

Dr. Furie said it could be that selecting sicker patients is a solution to this, as had been suggested in the subset analysis of the anifrolumab studies – which he was involved in – that identified differences in the response rates between interferon-high and interferon-low patients.

But if that was the case, the challenge would be recruiting enough of any particular subset of patients. For example, relatively few patients in the anifrolumab trial were classified as interferon low.

If the interferon expression levels are a marker for patients who are sicker, that could serve as a way to better select patients for clinical trials, he said. But it would also make it harder to achieve recruitment targets.

“I think the major problem in SLE trials is that patients have inflated activity scores, so you can gain SLEDAI scores with a little alopecia and an oral ulcer,” he said. “You can start eliminating those parameters from counting towards entry, but then as soon as you do that, you’re going to have trouble recruiting.”

Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and anifrolumab manufacturer AstraZeneca. Dr. Furie reported financial relationships with Genentech/Roche, GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda.

SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).

“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.

Furie_Richard_A_NY_web.jpg

The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.

It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
 

More potent B-cell depletion with obinutuzumab

Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.

The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.

That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.

“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.

163867_Merrill_Joan_web.PNG

Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.

Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”

However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
 

Newer strategies for greater B-cell depletion

A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.

And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.

“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”

Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.

“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.

Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.

SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).

“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.

Furie_Richard_A_NY_web.jpg

The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.

It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
 

More potent B-cell depletion with obinutuzumab

Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.

The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.

That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.

“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.

163867_Merrill_Joan_web.PNG

Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.

Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”

However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
 

Newer strategies for greater B-cell depletion

A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.

And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.

“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”

Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.

“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.

Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.

SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).

“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.

Furie_Richard_A_NY_web.jpg

The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.

It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
 

More potent B-cell depletion with obinutuzumab

Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.

The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.

That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.

“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.

163867_Merrill_Joan_web.PNG

Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.

Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”

However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.
 

Newer strategies for greater B-cell depletion

A third strategy for achieving greater B-cell depletion is bispecific T-cell engagers, or BiTEs. “I called it a ‘frenemy,’ where it’s taking the activated T cell and introducing it to the B cell, and it can kill it via direct T-cell killing,” Dr. Furie said in an interview. Mosunetuzumab (Lunsumio) is one example, and is currently in a phase 1 clinical trial of patients with SLE.

And the fourth strategy, which has proved so successful in lymphoma, is chimeric antigen receptor T-cell therapy (CAR T). Dr. Furie cited the recent publication of data from a CAR T clinical trial in five patients with refractory SLE. He said the data were impressive but the question for this treatment approach will be which patients are most likely to benefit and whether CAR T will experience the same ceiling effect because of pre-existing kidney damage.

“We won’t be seeing 100% response rates,” he said. “What we’ll be seeing, as a maximum, might be about 70%.” The big question for B-cell depletion in lupus was therefore how best to achieve it. “Is the future a potent monoclonal antibody, or is it in fact CAR T?”

Dr. Merrill said the analyses from B-cell depletion trials, showing greater response rates among more complete depleters, highlighted the importance of a personalized approach to treating lupus.

“One size fits all is never optimal in any disease, but it will prove a nonstarter in lupus, where we ought to be trying to find the optimal treatment regimen for each patient guided by biomarkers,” she said in an interview.

Dr. Furie reported having financial relationships with Genentech/Roche, which manufactures obinutuzumab and rituximab, as well as GlaxoSmithKline, Kezar Life Sciences, Kyverna Therapeutics, and Takeda. Dr. Merrill reported consulting for and receiving research support from a range of pharmaceutical companies including Genentech/Roche, GlaxoSmithKline, Pfizer, Janssen, Bristol-Myers Squibb, AbbVie, and AstraZeneca.

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

163571_Navarra_Sandra_web.jpg

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

163571_Navarra_Sandra_web.jpg

SEOUL, SOUTH KOREA – A once-daily, oral dose of the investigational drug cenerimod, developed for the treatment of systemic lupus erythematosus, has shown a greater response rate among individuals with more severe disease, according to data presented at an international congress on SLE.

Cenerimod is a potent, highly-selective sphingosine 1–phosphate receptor 1 (S1P1) modulator with attenuated calcium signaling, which targets an important signaling molecule in immunity and cell migration, said rheumatologist Sandra Navarra, MD, of the University of Santo Tomas Hospital and St. Luke’s Medical Center in Manila, Philippines.

163571_Navarra_Sandra_web.jpg

SEOUL, SOUTH KOREA – Nearly 8% of people with lupus nephritis who achieve complete remission of disease within 1 year of starting treatment will still go on to develop advanced chronic kidney disease (CKD), according to a presentation at an international congress on systemic lupus erythematosus.

Rheumatologist Dafna Gladman, MD, professor of medicine at the University of Toronto and codirector of the Lupus Clinic at Toronto Western Hospital, showed data from the Lupus Clinic’s prospective longitudinal cohort study in 273 patients with confirmed lupus nephritis who achieved complete remission within 12 months of baseline.

163550_Gladman_Dafna_web.jpg

Remission was defined as less than 0.5 g proteinuria over 24 hours, inactive urinary sediment, and serum creatinine less than 120% of baseline.

Of this group, 21 (7.7%) progressed to advanced CKD during follow-up, which ranged from 0.7 to 31.7 years with a median of 5.8 years, after enrollment.

Patients who had experienced at least one flare during their first 5 years were around 4.5 times more likely to progress to advanced CKD than were those who did not experience a flare.

While the study excluded patients who already had advanced CKD, the analysis found those with evidence of impaired kidney function at baseline also had more than a fourfold higher risk of developing advanced CKD.

Other significant risk factors for progression were having low complement C3 levels at baseline and having had a longer duration of disease before enrollment.

“Those patients already have abnormal renal function, so the message is that patients who are already in trouble, you’ve got to watch them very carefully,” Dr. Gladman said in an interview.

[embed:render:related:node:263119]

The study also looked at whether there was a difference between patients who developed advanced CKD earlier – before the median of 5.8 years – or later. While the numbers were small, Dr. Gladman said patients who progressed earlier tended to be older and were more likely to be on antihypertensive treatment and have lower estimated glomerular filtration rate and a lower Systemic Lupus Erythematosus Disease Activity Index–2K, compared with those who progressed later. Some patients also were noncompliant and/or experienced concomitant infections; four had moderate to severe interstitial fibrosis and tubular atrophy.

“We conclude that such patients should be monitored closely despite early remission, and we also highlight the importance of maintenance therapy, which should be communicated to the patients to prevent noncompliance and subsequent flare,” Dr. Gladman told the conference.

Dr. Gladman said her clinic told patients from the very beginning of their treatment that they would need to be seen at 2- to 6-month intervals, regardless of how well their disease was doing.

Commenting on the presentation, rheumatologist Mandana Nikpour MD, PhD, of St. Vincent’s Hospital in Melbourne, said the findings showed the importance of keeping a close eye on patients with lupus nephritis, even if their disease appears to be in remission.

“If you’ve had nephritis, and you go into remission, you may already have a degree of damage in your kidneys,” said Dr. Nikpour, also from the University of Melbourne. “If there’s a degree of uncontrolled hypertension, or if a patient is noncompliant with their treatment, and there’s a degree of grumbling disease activity, that can all conspire and add up to result in long-term kidney damage and loss of renal function.”

Dr. Gladman has received grants or research support from, or has consulted for, Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Bristol-Myers Squibb, Galapagos, and Gilead.

SEOUL, SOUTH KOREA – Nearly 8% of people with lupus nephritis who achieve complete remission of disease within 1 year of starting treatment will still go on to develop advanced chronic kidney disease (CKD), according to a presentation at an international congress on systemic lupus erythematosus.

Rheumatologist Dafna Gladman, MD, professor of medicine at the University of Toronto and codirector of the Lupus Clinic at Toronto Western Hospital, showed data from the Lupus Clinic’s prospective longitudinal cohort study in 273 patients with confirmed lupus nephritis who achieved complete remission within 12 months of baseline.

163550_Gladman_Dafna_web.jpg

Remission was defined as less than 0.5 g proteinuria over 24 hours, inactive urinary sediment, and serum creatinine less than 120% of baseline.

Of this group, 21 (7.7%) progressed to advanced CKD during follow-up, which ranged from 0.7 to 31.7 years with a median of 5.8 years, after enrollment.

Patients who had experienced at least one flare during their first 5 years were around 4.5 times more likely to progress to advanced CKD than were those who did not experience a flare.

While the study excluded patients who already had advanced CKD, the analysis found those with evidence of impaired kidney function at baseline also had more than a fourfold higher risk of developing advanced CKD.

Other significant risk factors for progression were having low complement C3 levels at baseline and having had a longer duration of disease before enrollment.

“Those patients already have abnormal renal function, so the message is that patients who are already in trouble, you’ve got to watch them very carefully,” Dr. Gladman said in an interview.

[embed:render:related:node:263119]

The study also looked at whether there was a difference between patients who developed advanced CKD earlier – before the median of 5.8 years – or later. While the numbers were small, Dr. Gladman said patients who progressed earlier tended to be older and were more likely to be on antihypertensive treatment and have lower estimated glomerular filtration rate and a lower Systemic Lupus Erythematosus Disease Activity Index–2K, compared with those who progressed later. Some patients also were noncompliant and/or experienced concomitant infections; four had moderate to severe interstitial fibrosis and tubular atrophy.

“We conclude that such patients should be monitored closely despite early remission, and we also highlight the importance of maintenance therapy, which should be communicated to the patients to prevent noncompliance and subsequent flare,” Dr. Gladman told the conference.

Dr. Gladman said her clinic told patients from the very beginning of their treatment that they would need to be seen at 2- to 6-month intervals, regardless of how well their disease was doing.

Commenting on the presentation, rheumatologist Mandana Nikpour MD, PhD, of St. Vincent’s Hospital in Melbourne, said the findings showed the importance of keeping a close eye on patients with lupus nephritis, even if their disease appears to be in remission.

“If you’ve had nephritis, and you go into remission, you may already have a degree of damage in your kidneys,” said Dr. Nikpour, also from the University of Melbourne. “If there’s a degree of uncontrolled hypertension, or if a patient is noncompliant with their treatment, and there’s a degree of grumbling disease activity, that can all conspire and add up to result in long-term kidney damage and loss of renal function.”

Dr. Gladman has received grants or research support from, or has consulted for, Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Bristol-Myers Squibb, Galapagos, and Gilead.

SEOUL, SOUTH KOREA – Nearly 8% of people with lupus nephritis who achieve complete remission of disease within 1 year of starting treatment will still go on to develop advanced chronic kidney disease (CKD), according to a presentation at an international congress on systemic lupus erythematosus.

Rheumatologist Dafna Gladman, MD, professor of medicine at the University of Toronto and codirector of the Lupus Clinic at Toronto Western Hospital, showed data from the Lupus Clinic’s prospective longitudinal cohort study in 273 patients with confirmed lupus nephritis who achieved complete remission within 12 months of baseline.

163550_Gladman_Dafna_web.jpg

Remission was defined as less than 0.5 g proteinuria over 24 hours, inactive urinary sediment, and serum creatinine less than 120% of baseline.

Of this group, 21 (7.7%) progressed to advanced CKD during follow-up, which ranged from 0.7 to 31.7 years with a median of 5.8 years, after enrollment.

Patients who had experienced at least one flare during their first 5 years were around 4.5 times more likely to progress to advanced CKD than were those who did not experience a flare.

While the study excluded patients who already had advanced CKD, the analysis found those with evidence of impaired kidney function at baseline also had more than a fourfold higher risk of developing advanced CKD.

Other significant risk factors for progression were having low complement C3 levels at baseline and having had a longer duration of disease before enrollment.

“Those patients already have abnormal renal function, so the message is that patients who are already in trouble, you’ve got to watch them very carefully,” Dr. Gladman said in an interview.

[embed:render:related:node:263119]

The study also looked at whether there was a difference between patients who developed advanced CKD earlier – before the median of 5.8 years – or later. While the numbers were small, Dr. Gladman said patients who progressed earlier tended to be older and were more likely to be on antihypertensive treatment and have lower estimated glomerular filtration rate and a lower Systemic Lupus Erythematosus Disease Activity Index–2K, compared with those who progressed later. Some patients also were noncompliant and/or experienced concomitant infections; four had moderate to severe interstitial fibrosis and tubular atrophy.

“We conclude that such patients should be monitored closely despite early remission, and we also highlight the importance of maintenance therapy, which should be communicated to the patients to prevent noncompliance and subsequent flare,” Dr. Gladman told the conference.

Dr. Gladman said her clinic told patients from the very beginning of their treatment that they would need to be seen at 2- to 6-month intervals, regardless of how well their disease was doing.

Commenting on the presentation, rheumatologist Mandana Nikpour MD, PhD, of St. Vincent’s Hospital in Melbourne, said the findings showed the importance of keeping a close eye on patients with lupus nephritis, even if their disease appears to be in remission.

“If you’ve had nephritis, and you go into remission, you may already have a degree of damage in your kidneys,” said Dr. Nikpour, also from the University of Melbourne. “If there’s a degree of uncontrolled hypertension, or if a patient is noncompliant with their treatment, and there’s a degree of grumbling disease activity, that can all conspire and add up to result in long-term kidney damage and loss of renal function.”

Dr. Gladman has received grants or research support from, or has consulted for, Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Bristol-Myers Squibb, Galapagos, and Gilead.

SEOUL, SOUTH KOREA – A panel of urinary biomarkers may do better than measuring proteinuria in predicting which patients with lupus nephritis are going to respond to treatment, according to a presentation at an international congress on systemic lupus erythematosus.

Physician-scientist Andrea Fava, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, presented data from a study using urine proteomics to identify biomarkers present in the urine of patients with lupus nephritis at 3 months after starting treatment that were linked to better outcomes from that treatment at 1 year.

While proteinuria is the standard measure used to guide decisions about whether to do a kidney biopsy and how to treat lupus nephritis, it doesn’t always correlate with what’s actually going on inside the kidney in terms of histology and inflammation, Dr. Fava said.

Fava_Andrea_MD_web.jpg

He pointed to an earlier study in which researchers did kidney biopsies 6 months after patients with lupus nephritis started treatment with mycophenolate. This suggested that around half of patients who showed a clinical response to treatment – defined as proteinuria below 500 mg/day – still had significant histologic disease activity. Another study suggested that this elevated histologic disease activity is associated with a risk of flare, which can result in significant nephron loss. On the flip side, nearly two-thirds of patients in complete histologic remission still had elevated proteinuria.

Unfortunately, it’s not possible or practical to biopsy patients on a regular basis, Dr. Fava said. “So we need better biomarkers, and to do so, we need better knowledge of the pathophysiology because if we have biomarkers that reflect tissue biology in real-time, that may surely guide personalized treatments,” he said at the congress.

Dr. Fava and colleagues enrolled 225 patients with SLE who were undergoing kidney biopsy and 10 healthy controls and used proteomics to quantify the urinary levels of around 1,200 proteins at baseline, 3, 6, and 12 months after initiating treatment.

The team then analyzed these data to look for protein signatures that correlated with histologic phenotypes – particularly the amount of inflammation in the kidney – and clinical features such as response to treatment.

They found several protein biomarkers that appeared to be linked to histologic activity in the kidney, including interleukin (IL)-16, CD163, and neutrophil granule proteins.

Initially, the team looked at baseline levels of these proteins to see if they predicted who responded to treatment, but found no difference between responders and nonresponders.

However, when they looked at levels at 3 months after treatment, a pattern emerged. “We found that in patients who were not responding, there were no changes after 3 months of treatment in the urine proteome,” Dr. Fava said. Among those who did respond to treatment, the levels of these proteins – IL-16, CD163, galectin-1, and CD206 – decreased significantly.

[embed:render:related:node:261207]

“So the proteins that are linked to renal activity decrease only in responders, suggesting that effective immunosuppression is effective in reducing intrarenal inflammation, which eventually results in low proteinuria at 1 year.”

The decline in these biomarkers persisted at 1 year, and the study suggested it was a better predictor of which patients would respond to treatment at 1 year than proteinuria.

Dr. Fava said in an interview that better biomarkers could revolutionize the treatment and management of lupus nephritis.

“First of all, it can shift the management strategy from treatment to prevention, because at the very beginning we can nip it in the bud maybe with very gentle treatment,” he said. Different panels of urine biomarkers could identify patients at risk of treatment failure, and also help patients to taper off their immunosuppressive therapy without an increased risk of flare. “If we have a way to tell us there’s still inflammation that needs treatment, that could change the way we do it,” he said.

He acknowledged there are significant challenges to developing these biomarkers for clinical use; one is the decision of how to define disease activity without relying on proteinuria as a measure. “Why do I want a biomarker that can predict another biomarker?” he said.

Another presentation during the same session, by Huihua Ding, MD, of Shanghai Jiao Tong University in Shanghai, China, reported on the use of urinary L-selectin to assess renal disease activity and response to treatment in a multiethnic cohort.

This study, involving 474 patients with SLE with or without renal involvement in the United States and China, found levels of urinary L-selectin were elevated only in patients with active lupus nephritis and showed patterns that correlated with renal histologic characteristics.

Morand_Eric_F_AUSTRALIA_web.jpg

Clinical rheumatologist Eric F. Morand, MD, PhD, and head of the School of Clinical Sciences at Monash University in Melbourne said one challenge with using urinary biomarkers was that it was not yet clear what these biomarkers reveal about the kidney. “It will be important to see whether this proteomic data actually link to renal outcomes,” Dr. Morand said in an interview. “I think predicting the response to treatment should be based around GFR [glomerular filtration rate] preservation, and I don’t think I’ve seen data yet that the urine biomarkers are going to tell us how to do that better.”

Dr. Morand is optimistic that urine biomarkers will one day be able to achieve that, but he stressed the importance of having urine biomarker tests available in the field at low cost. “You’re going to be doing the tests repeatedly, so therefore, you’re probably going to need to come down to a smaller list of proteins that you measure.”

Dr. Fava reported receiving support from Sanofi and Annexion Bio.

SEOUL, SOUTH KOREA – A panel of urinary biomarkers may do better than measuring proteinuria in predicting which patients with lupus nephritis are going to respond to treatment, according to a presentation at an international congress on systemic lupus erythematosus.

Physician-scientist Andrea Fava, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, presented data from a study using urine proteomics to identify biomarkers present in the urine of patients with lupus nephritis at 3 months after starting treatment that were linked to better outcomes from that treatment at 1 year.

While proteinuria is the standard measure used to guide decisions about whether to do a kidney biopsy and how to treat lupus nephritis, it doesn’t always correlate with what’s actually going on inside the kidney in terms of histology and inflammation, Dr. Fava said.

Fava_Andrea_MD_web.jpg

He pointed to an earlier study in which researchers did kidney biopsies 6 months after patients with lupus nephritis started treatment with mycophenolate. This suggested that around half of patients who showed a clinical response to treatment – defined as proteinuria below 500 mg/day – still had significant histologic disease activity. Another study suggested that this elevated histologic disease activity is associated with a risk of flare, which can result in significant nephron loss. On the flip side, nearly two-thirds of patients in complete histologic remission still had elevated proteinuria.

Unfortunately, it’s not possible or practical to biopsy patients on a regular basis, Dr. Fava said. “So we need better biomarkers, and to do so, we need better knowledge of the pathophysiology because if we have biomarkers that reflect tissue biology in real-time, that may surely guide personalized treatments,” he said at the congress.

Dr. Fava and colleagues enrolled 225 patients with SLE who were undergoing kidney biopsy and 10 healthy controls and used proteomics to quantify the urinary levels of around 1,200 proteins at baseline, 3, 6, and 12 months after initiating treatment.

The team then analyzed these data to look for protein signatures that correlated with histologic phenotypes – particularly the amount of inflammation in the kidney – and clinical features such as response to treatment.

They found several protein biomarkers that appeared to be linked to histologic activity in the kidney, including interleukin (IL)-16, CD163, and neutrophil granule proteins.

Initially, the team looked at baseline levels of these proteins to see if they predicted who responded to treatment, but found no difference between responders and nonresponders.

However, when they looked at levels at 3 months after treatment, a pattern emerged. “We found that in patients who were not responding, there were no changes after 3 months of treatment in the urine proteome,” Dr. Fava said. Among those who did respond to treatment, the levels of these proteins – IL-16, CD163, galectin-1, and CD206 – decreased significantly.

[embed:render:related:node:261207]

“So the proteins that are linked to renal activity decrease only in responders, suggesting that effective immunosuppression is effective in reducing intrarenal inflammation, which eventually results in low proteinuria at 1 year.”

The decline in these biomarkers persisted at 1 year, and the study suggested it was a better predictor of which patients would respond to treatment at 1 year than proteinuria.

Dr. Fava said in an interview that better biomarkers could revolutionize the treatment and management of lupus nephritis.

“First of all, it can shift the management strategy from treatment to prevention, because at the very beginning we can nip it in the bud maybe with very gentle treatment,” he said. Different panels of urine biomarkers could identify patients at risk of treatment failure, and also help patients to taper off their immunosuppressive therapy without an increased risk of flare. “If we have a way to tell us there’s still inflammation that needs treatment, that could change the way we do it,” he said.

He acknowledged there are significant challenges to developing these biomarkers for clinical use; one is the decision of how to define disease activity without relying on proteinuria as a measure. “Why do I want a biomarker that can predict another biomarker?” he said.

Another presentation during the same session, by Huihua Ding, MD, of Shanghai Jiao Tong University in Shanghai, China, reported on the use of urinary L-selectin to assess renal disease activity and response to treatment in a multiethnic cohort.

This study, involving 474 patients with SLE with or without renal involvement in the United States and China, found levels of urinary L-selectin were elevated only in patients with active lupus nephritis and showed patterns that correlated with renal histologic characteristics.

Morand_Eric_F_AUSTRALIA_web.jpg

Clinical rheumatologist Eric F. Morand, MD, PhD, and head of the School of Clinical Sciences at Monash University in Melbourne said one challenge with using urinary biomarkers was that it was not yet clear what these biomarkers reveal about the kidney. “It will be important to see whether this proteomic data actually link to renal outcomes,” Dr. Morand said in an interview. “I think predicting the response to treatment should be based around GFR [glomerular filtration rate] preservation, and I don’t think I’ve seen data yet that the urine biomarkers are going to tell us how to do that better.”

Dr. Morand is optimistic that urine biomarkers will one day be able to achieve that, but he stressed the importance of having urine biomarker tests available in the field at low cost. “You’re going to be doing the tests repeatedly, so therefore, you’re probably going to need to come down to a smaller list of proteins that you measure.”

Dr. Fava reported receiving support from Sanofi and Annexion Bio.

SEOUL, SOUTH KOREA – A panel of urinary biomarkers may do better than measuring proteinuria in predicting which patients with lupus nephritis are going to respond to treatment, according to a presentation at an international congress on systemic lupus erythematosus.

Physician-scientist Andrea Fava, MD, of the division of rheumatology at Johns Hopkins University, Baltimore, presented data from a study using urine proteomics to identify biomarkers present in the urine of patients with lupus nephritis at 3 months after starting treatment that were linked to better outcomes from that treatment at 1 year.

While proteinuria is the standard measure used to guide decisions about whether to do a kidney biopsy and how to treat lupus nephritis, it doesn’t always correlate with what’s actually going on inside the kidney in terms of histology and inflammation, Dr. Fava said.

Fava_Andrea_MD_web.jpg

He pointed to an earlier study in which researchers did kidney biopsies 6 months after patients with lupus nephritis started treatment with mycophenolate. This suggested that around half of patients who showed a clinical response to treatment – defined as proteinuria below 500 mg/day – still had significant histologic disease activity. Another study suggested that this elevated histologic disease activity is associated with a risk of flare, which can result in significant nephron loss. On the flip side, nearly two-thirds of patients in complete histologic remission still had elevated proteinuria.

Unfortunately, it’s not possible or practical to biopsy patients on a regular basis, Dr. Fava said. “So we need better biomarkers, and to do so, we need better knowledge of the pathophysiology because if we have biomarkers that reflect tissue biology in real-time, that may surely guide personalized treatments,” he said at the congress.

Dr. Fava and colleagues enrolled 225 patients with SLE who were undergoing kidney biopsy and 10 healthy controls and used proteomics to quantify the urinary levels of around 1,200 proteins at baseline, 3, 6, and 12 months after initiating treatment.

The team then analyzed these data to look for protein signatures that correlated with histologic phenotypes – particularly the amount of inflammation in the kidney – and clinical features such as response to treatment.

They found several protein biomarkers that appeared to be linked to histologic activity in the kidney, including interleukin (IL)-16, CD163, and neutrophil granule proteins.

Initially, the team looked at baseline levels of these proteins to see if they predicted who responded to treatment, but found no difference between responders and nonresponders.

However, when they looked at levels at 3 months after treatment, a pattern emerged. “We found that in patients who were not responding, there were no changes after 3 months of treatment in the urine proteome,” Dr. Fava said. Among those who did respond to treatment, the levels of these proteins – IL-16, CD163, galectin-1, and CD206 – decreased significantly.

[embed:render:related:node:261207]

“So the proteins that are linked to renal activity decrease only in responders, suggesting that effective immunosuppression is effective in reducing intrarenal inflammation, which eventually results in low proteinuria at 1 year.”

The decline in these biomarkers persisted at 1 year, and the study suggested it was a better predictor of which patients would respond to treatment at 1 year than proteinuria.

Dr. Fava said in an interview that better biomarkers could revolutionize the treatment and management of lupus nephritis.

“First of all, it can shift the management strategy from treatment to prevention, because at the very beginning we can nip it in the bud maybe with very gentle treatment,” he said. Different panels of urine biomarkers could identify patients at risk of treatment failure, and also help patients to taper off their immunosuppressive therapy without an increased risk of flare. “If we have a way to tell us there’s still inflammation that needs treatment, that could change the way we do it,” he said.

He acknowledged there are significant challenges to developing these biomarkers for clinical use; one is the decision of how to define disease activity without relying on proteinuria as a measure. “Why do I want a biomarker that can predict another biomarker?” he said.

Another presentation during the same session, by Huihua Ding, MD, of Shanghai Jiao Tong University in Shanghai, China, reported on the use of urinary L-selectin to assess renal disease activity and response to treatment in a multiethnic cohort.

This study, involving 474 patients with SLE with or without renal involvement in the United States and China, found levels of urinary L-selectin were elevated only in patients with active lupus nephritis and showed patterns that correlated with renal histologic characteristics.

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Clinical rheumatologist Eric F. Morand, MD, PhD, and head of the School of Clinical Sciences at Monash University in Melbourne said one challenge with using urinary biomarkers was that it was not yet clear what these biomarkers reveal about the kidney. “It will be important to see whether this proteomic data actually link to renal outcomes,” Dr. Morand said in an interview. “I think predicting the response to treatment should be based around GFR [glomerular filtration rate] preservation, and I don’t think I’ve seen data yet that the urine biomarkers are going to tell us how to do that better.”

Dr. Morand is optimistic that urine biomarkers will one day be able to achieve that, but he stressed the importance of having urine biomarker tests available in the field at low cost. “You’re going to be doing the tests repeatedly, so therefore, you’re probably going to need to come down to a smaller list of proteins that you measure.”

Dr. Fava reported receiving support from Sanofi and Annexion Bio.