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Two-drug dolutegravir treatment noninferior to 3/4 drug regimen
A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, presented at the virtual meeting of the International AIDS Society.
The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.
For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).
In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).
“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.
The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.
Trial details
The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.
All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.
The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.
In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.
Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.
Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.
There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.
Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.
Commenting on the research, Alexandra Calmy, PhD, of the HIV/AIDS Unit and LIPO & metabolism group, infectious disease division, Geneva University Hospitals, said that data on quality of life and patient satisfaction measures would be of particular interest.
“Indeed, it is not absolutely clear how a two-in-one versus a three-in-one pill may really influence treatment satisfaction and/or quality of life,” she said in an interview. “Validated scales and patient-reported outcomes with regards to treatment satisfaction would have been an added value to the study.”
Dr. Calmy coauthored a previous study looking at weight change and pharmacokinetic parameters in patients with HIV who switched to DTG-based regimens, and also found weight changes were increased with the DTG regimens. However, the weight gain was not associated with DTG plasma levels, thus supporting Dr. Llibre’s suggestion of possible withdrawal effects from other drugs.
STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment
In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.
The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.
In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.
While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.
“The STAT data is important as it shows us, for the first time, that in patients where potentially very little is known prior to treatment initiation, DTG/3TC can be very effectively used as a first-line regimen in a ‘test-and-treat’ approach without compromising on patient safety,” first author Charlotte-Paige Rolle, MD, director of research operations, Orlando (Fla.) Immunology Center, said in an interview.
Dr. Rolle added that “with careful monitoring of test results in the first weeks of therapy, we can appropriately and safely adjust therapy from DTG/3TC to a three-drug regimen if needed for patients that have transmitted drug resistance to DTG or 3TC, or hepatitis B coinfection, with both of these occurring at very low rates regardless.”
The SALSA and STAT studies received funding from ViiV Healthcare. Dr. Llibre has received honoraria or consultation fees from ViiV Healthcare, Gilead Sciences and Janssen-Cilag. Dr. Rolle has received grants from and served on advisory boards/speakers bureaus for ViiV Healthcare, Gilead, and Janssen. Dr. Calmy had no disclosures to report.
A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, presented at the virtual meeting of the International AIDS Society.
The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.
For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).
In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).
“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.
The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.
Trial details
The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.
All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.
The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.
In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.
Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.
Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.
There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.
Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.
Commenting on the research, Alexandra Calmy, PhD, of the HIV/AIDS Unit and LIPO & metabolism group, infectious disease division, Geneva University Hospitals, said that data on quality of life and patient satisfaction measures would be of particular interest.
“Indeed, it is not absolutely clear how a two-in-one versus a three-in-one pill may really influence treatment satisfaction and/or quality of life,” she said in an interview. “Validated scales and patient-reported outcomes with regards to treatment satisfaction would have been an added value to the study.”
Dr. Calmy coauthored a previous study looking at weight change and pharmacokinetic parameters in patients with HIV who switched to DTG-based regimens, and also found weight changes were increased with the DTG regimens. However, the weight gain was not associated with DTG plasma levels, thus supporting Dr. Llibre’s suggestion of possible withdrawal effects from other drugs.
STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment
In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.
The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.
In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.
While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.
“The STAT data is important as it shows us, for the first time, that in patients where potentially very little is known prior to treatment initiation, DTG/3TC can be very effectively used as a first-line regimen in a ‘test-and-treat’ approach without compromising on patient safety,” first author Charlotte-Paige Rolle, MD, director of research operations, Orlando (Fla.) Immunology Center, said in an interview.
Dr. Rolle added that “with careful monitoring of test results in the first weeks of therapy, we can appropriately and safely adjust therapy from DTG/3TC to a three-drug regimen if needed for patients that have transmitted drug resistance to DTG or 3TC, or hepatitis B coinfection, with both of these occurring at very low rates regardless.”
The SALSA and STAT studies received funding from ViiV Healthcare. Dr. Llibre has received honoraria or consultation fees from ViiV Healthcare, Gilead Sciences and Janssen-Cilag. Dr. Rolle has received grants from and served on advisory boards/speakers bureaus for ViiV Healthcare, Gilead, and Janssen. Dr. Calmy had no disclosures to report.
A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, presented at the virtual meeting of the International AIDS Society.
The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.
For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).
In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).
“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.
The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.
Trial details
The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.
All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.
The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.
In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.
Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.
Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.
There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.
Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.
Commenting on the research, Alexandra Calmy, PhD, of the HIV/AIDS Unit and LIPO & metabolism group, infectious disease division, Geneva University Hospitals, said that data on quality of life and patient satisfaction measures would be of particular interest.
“Indeed, it is not absolutely clear how a two-in-one versus a three-in-one pill may really influence treatment satisfaction and/or quality of life,” she said in an interview. “Validated scales and patient-reported outcomes with regards to treatment satisfaction would have been an added value to the study.”
Dr. Calmy coauthored a previous study looking at weight change and pharmacokinetic parameters in patients with HIV who switched to DTG-based regimens, and also found weight changes were increased with the DTG regimens. However, the weight gain was not associated with DTG plasma levels, thus supporting Dr. Llibre’s suggestion of possible withdrawal effects from other drugs.
STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment
In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.
The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.
In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.
While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.
“The STAT data is important as it shows us, for the first time, that in patients where potentially very little is known prior to treatment initiation, DTG/3TC can be very effectively used as a first-line regimen in a ‘test-and-treat’ approach without compromising on patient safety,” first author Charlotte-Paige Rolle, MD, director of research operations, Orlando (Fla.) Immunology Center, said in an interview.
Dr. Rolle added that “with careful monitoring of test results in the first weeks of therapy, we can appropriately and safely adjust therapy from DTG/3TC to a three-drug regimen if needed for patients that have transmitted drug resistance to DTG or 3TC, or hepatitis B coinfection, with both of these occurring at very low rates regardless.”
The SALSA and STAT studies received funding from ViiV Healthcare. Dr. Llibre has received honoraria or consultation fees from ViiV Healthcare, Gilead Sciences and Janssen-Cilag. Dr. Rolle has received grants from and served on advisory boards/speakers bureaus for ViiV Healthcare, Gilead, and Janssen. Dr. Calmy had no disclosures to report.
FROM IAS 2021
HIV-associated cryptococcal meningitis: Single-dose regimen found non-inferior
A single high dose of the antifungal agent liposomal amphotericin B (L-AmB; AmBisome, Gilead Sciences), with a background regimen of flucytosine and fluconazole, is non-inferior and significantly safer in preventing mortality in HIV-associated cryptococcal meningitis than a conventional seven-day regimen that is the current standard of care, according to a new study.
“The results of this phase 3 [AMBITION-cm] trial make it clear that this approach is just as good as the current World Health Organization-recommended first-line treatment in preventing death,” first author David S. Lawrence, MD, AMBITION study lead clinician, of the London School of Hygiene and Tropical Medicine, United Kingdom, said in an interview.
“The fact that this was the largest ever trial [on HIV-associated cryptococcal meningitis] conducted to date… gives us a high level of confidence in these results,” he said of the study, which was presented at the virtual annual meeting of the International AIDS Society.
“We believe that this should become the WHO-recommended first-line regimen,” he emphasized.
In commenting on the study, Meg Doherty, MD, PhD, director of global HIV, hepatitis, and STI programs at WHO, agreed that a shorter regimen could be vital, particularly in settings with limited resources.
“The results from the AMBITION trial are important for low- and middle-income countries, where the cost and complexity of implementing the current standard seven-day course of L-ambisome or cryptococcal meningitis treatment can put this out of reach for many,” she told this news organization.
“Simplification that maintains the highest quality of care is an important component of the public health approach for HIV treatment and care,” she added.
Dr. Doherty could not comment on any possible changes to WHO recommendations, which are formulated by an independent guideline development group, but a spokesperson said that “WHO is preparing an updated review of the evidence for treating cryptococcal disease as a first step towards updating guidance.”
Conventional treatment toxicities
Cryptococcal meningitis is a leading cause of death in HIV, and the conventional treatment of amphotericin B deoxycholate, though less expensive than L-AmB, is more toxic, causing anemia, renal impairment, and electrolyte abnormalities, Dr. Lawrence explained
Having previously shown a single 10 mg/kg dose of L-AmB to be as effective as the longer regimen of 14 daily doses in terms of clearing cryptococcus from the cerebrospinal fluid, Dr. Lawrence and his colleagues conducted the phase 3 AMBITION-Cm trial to evaluate the effect on mortality, enrolling 844 patients in Botswana, Malawi, South Africa, Uganda, and Zimbabwe who were HIV-positive and had a first episode of cryptococcal meningitis.
Participants in the study were randomized to treatment either with single, high-dose L-AmB (10 mg/kg), combined with 14 days of flucytosine 100 mg/kg/day and fluconazole 1,200 mg/day or to a control group receiving 7 daily doses of AmB deoxycholate (1 mg/kg) plus 7 days of flucytosine 100 mg/kg/day, followed by 7 days of fluconazole 1,200 mg/day.
All patients were also provided with consolidation therapy of fluconazole 800 mg/day for eight weeks. Of the patients, 60.2% were male, their median age was 37, and their median CD4 count was 27 cells/mm3.
For the primary endpoint in the intention-to-treat analysis of 814 patients, the 10-week mortality rate in the single-dose L-AmB group was 24.82% (101 of 407) and 28.75% (117 of 407) in the control arm, for a difference (-3.93%) that was well within the pre-specified non-inferiority margin of 10%.
As expected, the safety measures were significantly improved with the single-dose of L-AmB: Rates of grade 3 or 4 adverse events within the initial 21 days of treatment in the single-dose L-AmB group were 50% versus 62.3% in the control group, and severe anemia occurred in just 13% of single-dose L-AmB participants, compared with 41% in the AmB deoxycholate control arm (both P < .001), Dr. Lawrence reported.
Furthermore, the average decline in hemoglobin over the first week was 0.3 g/dL in the single-dose L-AmB arm and 1.9 g/dL in the control arm, resulting in the need for more blood transfusions in the control arm (P < .001).
The impact on kidney function was also worse in the higher dose arm, with an average increase in creatinine over the first week of 20.2% in the L-AmB group versus 49.7% in the control group, while hypokalemia and thrombophlebitis were also more common with the higher dose group, Dr. Lawrence noted.
In the adjusted analysis, the single-dose L-AmB measures were in fact superior after adjusting for factors including research site, age, sex, baseline Glasgow Coma Scale, CD4 count, CSF cryptococcal colony-forming units/mL, antiretroviral therapy status, hemoglobin, and CSF opening pressure.
Mortality rate still high – but significantly reduced
The mortality rate of about 25% in the study after the treatment is still significantly higher than typically seen in high-income countries such as the United States, where HIV-associated cryptococcal meningitis is less common and associated with a mortality of roughly 10-15%, Dr. Lawrence noted.
The rate is nevertheless among the lowest mortality rates ever reported within a clinical trial conducted in resource-limited settings, he explained.
“These results are a step in the right direction and a significant improvement on the rates of 40% to 45% reported with two-week L-AmB-based regimens in African settings,” Dr. Lawrence underscored.
Higher cost — but potentially more cost-effective
With a higher cost than AmB deoxycholate, L-AmB’s utilization in resource-limited settings has been a challenge: A single vial of L-AmB ranges from $80 to $200, according to some reports, and while 14-day dosing requires as many as 42 vials of L-AmB, even a 7-day regimen still requires 21 vials.
In comparison, the single-dose L-AmB regimen only requires an average of 10 to 11 vials per patient, but the regimen’s higher safety could translate to far greater cost savings, Dr. Lawrence explained.
“While the AmBisome regimen is technically more expensive in terms of drugs, we expect it to be cost-effective or possibly cost-saving when taking into account that there is less toxicity, fewer blood tests, less transfusions, etc., and possibly shorter duration of hospital admission,” he said.
Cost, supply controversy: ‘Black fungus’-related demand
The drug’s cost — as well as supply issues — have meanwhile become even more of a problem as L-AmB has unexpectedly also become urgently needed in the treatment of mucormycosis in India and Nepal, where the otherwise rare fungal disease, commonly known as “black fungus,” has been increasingly affecting COVID-19 patients and survivors.
Gilead had previously announced in 2018 its intention to make L-AmB more widely available at a price of $16.25 per vial, but “implementation of this has been slow,” Dr. Lawrence said.
As a result, Gilead is facing heightened pressure to implement the lower prices – and also improve substantial supply issues, with Médecins Sans Frontières (Doctors Without Borders) and dozens of other global organizations issuing an open letter to Gilead and partner Viatris in June calling for immediate action to implement the lower price and improve supply of L-AmB.
In a company statement, Gilead responded, detailing its “commit[ment] to the non-profit pricing for the treatment of cryptococcal meningitis” and to efforts to improve the public health crisis in India.
For their part, Dr. Lawrence and his colleagues are working on producing more research on the issue.
“We hope that the conclusive results of the AMBITION trial will give a much needed push to implement this program,” he said.
“We are also currently completing the cost-effectiveness analysis of the study, which we hope will provide additional evidence to support widespread implementation of this regimen and highlight further the urgent need to broaden access to AmBisome and flucytosine,” he said.
The trial was supported by a grant through the European Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (SIDA) (TRIA2015-1092), and the Wellcome Trust / Medical Research Council (UK)/UKAID Joint Global Health Trials (MR/P006922/1. The AmBisome was donated by Gilead Sciences. Dr. Lawrence had no disclosures to report.
A single high dose of the antifungal agent liposomal amphotericin B (L-AmB; AmBisome, Gilead Sciences), with a background regimen of flucytosine and fluconazole, is non-inferior and significantly safer in preventing mortality in HIV-associated cryptococcal meningitis than a conventional seven-day regimen that is the current standard of care, according to a new study.
“The results of this phase 3 [AMBITION-cm] trial make it clear that this approach is just as good as the current World Health Organization-recommended first-line treatment in preventing death,” first author David S. Lawrence, MD, AMBITION study lead clinician, of the London School of Hygiene and Tropical Medicine, United Kingdom, said in an interview.
“The fact that this was the largest ever trial [on HIV-associated cryptococcal meningitis] conducted to date… gives us a high level of confidence in these results,” he said of the study, which was presented at the virtual annual meeting of the International AIDS Society.
“We believe that this should become the WHO-recommended first-line regimen,” he emphasized.
In commenting on the study, Meg Doherty, MD, PhD, director of global HIV, hepatitis, and STI programs at WHO, agreed that a shorter regimen could be vital, particularly in settings with limited resources.
“The results from the AMBITION trial are important for low- and middle-income countries, where the cost and complexity of implementing the current standard seven-day course of L-ambisome or cryptococcal meningitis treatment can put this out of reach for many,” she told this news organization.
“Simplification that maintains the highest quality of care is an important component of the public health approach for HIV treatment and care,” she added.
Dr. Doherty could not comment on any possible changes to WHO recommendations, which are formulated by an independent guideline development group, but a spokesperson said that “WHO is preparing an updated review of the evidence for treating cryptococcal disease as a first step towards updating guidance.”
Conventional treatment toxicities
Cryptococcal meningitis is a leading cause of death in HIV, and the conventional treatment of amphotericin B deoxycholate, though less expensive than L-AmB, is more toxic, causing anemia, renal impairment, and electrolyte abnormalities, Dr. Lawrence explained
Having previously shown a single 10 mg/kg dose of L-AmB to be as effective as the longer regimen of 14 daily doses in terms of clearing cryptococcus from the cerebrospinal fluid, Dr. Lawrence and his colleagues conducted the phase 3 AMBITION-Cm trial to evaluate the effect on mortality, enrolling 844 patients in Botswana, Malawi, South Africa, Uganda, and Zimbabwe who were HIV-positive and had a first episode of cryptococcal meningitis.
Participants in the study were randomized to treatment either with single, high-dose L-AmB (10 mg/kg), combined with 14 days of flucytosine 100 mg/kg/day and fluconazole 1,200 mg/day or to a control group receiving 7 daily doses of AmB deoxycholate (1 mg/kg) plus 7 days of flucytosine 100 mg/kg/day, followed by 7 days of fluconazole 1,200 mg/day.
All patients were also provided with consolidation therapy of fluconazole 800 mg/day for eight weeks. Of the patients, 60.2% were male, their median age was 37, and their median CD4 count was 27 cells/mm3.
For the primary endpoint in the intention-to-treat analysis of 814 patients, the 10-week mortality rate in the single-dose L-AmB group was 24.82% (101 of 407) and 28.75% (117 of 407) in the control arm, for a difference (-3.93%) that was well within the pre-specified non-inferiority margin of 10%.
As expected, the safety measures were significantly improved with the single-dose of L-AmB: Rates of grade 3 or 4 adverse events within the initial 21 days of treatment in the single-dose L-AmB group were 50% versus 62.3% in the control group, and severe anemia occurred in just 13% of single-dose L-AmB participants, compared with 41% in the AmB deoxycholate control arm (both P < .001), Dr. Lawrence reported.
Furthermore, the average decline in hemoglobin over the first week was 0.3 g/dL in the single-dose L-AmB arm and 1.9 g/dL in the control arm, resulting in the need for more blood transfusions in the control arm (P < .001).
The impact on kidney function was also worse in the higher dose arm, with an average increase in creatinine over the first week of 20.2% in the L-AmB group versus 49.7% in the control group, while hypokalemia and thrombophlebitis were also more common with the higher dose group, Dr. Lawrence noted.
In the adjusted analysis, the single-dose L-AmB measures were in fact superior after adjusting for factors including research site, age, sex, baseline Glasgow Coma Scale, CD4 count, CSF cryptococcal colony-forming units/mL, antiretroviral therapy status, hemoglobin, and CSF opening pressure.
Mortality rate still high – but significantly reduced
The mortality rate of about 25% in the study after the treatment is still significantly higher than typically seen in high-income countries such as the United States, where HIV-associated cryptococcal meningitis is less common and associated with a mortality of roughly 10-15%, Dr. Lawrence noted.
The rate is nevertheless among the lowest mortality rates ever reported within a clinical trial conducted in resource-limited settings, he explained.
“These results are a step in the right direction and a significant improvement on the rates of 40% to 45% reported with two-week L-AmB-based regimens in African settings,” Dr. Lawrence underscored.
Higher cost — but potentially more cost-effective
With a higher cost than AmB deoxycholate, L-AmB’s utilization in resource-limited settings has been a challenge: A single vial of L-AmB ranges from $80 to $200, according to some reports, and while 14-day dosing requires as many as 42 vials of L-AmB, even a 7-day regimen still requires 21 vials.
In comparison, the single-dose L-AmB regimen only requires an average of 10 to 11 vials per patient, but the regimen’s higher safety could translate to far greater cost savings, Dr. Lawrence explained.
“While the AmBisome regimen is technically more expensive in terms of drugs, we expect it to be cost-effective or possibly cost-saving when taking into account that there is less toxicity, fewer blood tests, less transfusions, etc., and possibly shorter duration of hospital admission,” he said.
Cost, supply controversy: ‘Black fungus’-related demand
The drug’s cost — as well as supply issues — have meanwhile become even more of a problem as L-AmB has unexpectedly also become urgently needed in the treatment of mucormycosis in India and Nepal, where the otherwise rare fungal disease, commonly known as “black fungus,” has been increasingly affecting COVID-19 patients and survivors.
Gilead had previously announced in 2018 its intention to make L-AmB more widely available at a price of $16.25 per vial, but “implementation of this has been slow,” Dr. Lawrence said.
As a result, Gilead is facing heightened pressure to implement the lower prices – and also improve substantial supply issues, with Médecins Sans Frontières (Doctors Without Borders) and dozens of other global organizations issuing an open letter to Gilead and partner Viatris in June calling for immediate action to implement the lower price and improve supply of L-AmB.
In a company statement, Gilead responded, detailing its “commit[ment] to the non-profit pricing for the treatment of cryptococcal meningitis” and to efforts to improve the public health crisis in India.
For their part, Dr. Lawrence and his colleagues are working on producing more research on the issue.
“We hope that the conclusive results of the AMBITION trial will give a much needed push to implement this program,” he said.
“We are also currently completing the cost-effectiveness analysis of the study, which we hope will provide additional evidence to support widespread implementation of this regimen and highlight further the urgent need to broaden access to AmBisome and flucytosine,” he said.
The trial was supported by a grant through the European Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (SIDA) (TRIA2015-1092), and the Wellcome Trust / Medical Research Council (UK)/UKAID Joint Global Health Trials (MR/P006922/1. The AmBisome was donated by Gilead Sciences. Dr. Lawrence had no disclosures to report.
A single high dose of the antifungal agent liposomal amphotericin B (L-AmB; AmBisome, Gilead Sciences), with a background regimen of flucytosine and fluconazole, is non-inferior and significantly safer in preventing mortality in HIV-associated cryptococcal meningitis than a conventional seven-day regimen that is the current standard of care, according to a new study.
“The results of this phase 3 [AMBITION-cm] trial make it clear that this approach is just as good as the current World Health Organization-recommended first-line treatment in preventing death,” first author David S. Lawrence, MD, AMBITION study lead clinician, of the London School of Hygiene and Tropical Medicine, United Kingdom, said in an interview.
“The fact that this was the largest ever trial [on HIV-associated cryptococcal meningitis] conducted to date… gives us a high level of confidence in these results,” he said of the study, which was presented at the virtual annual meeting of the International AIDS Society.
“We believe that this should become the WHO-recommended first-line regimen,” he emphasized.
In commenting on the study, Meg Doherty, MD, PhD, director of global HIV, hepatitis, and STI programs at WHO, agreed that a shorter regimen could be vital, particularly in settings with limited resources.
“The results from the AMBITION trial are important for low- and middle-income countries, where the cost and complexity of implementing the current standard seven-day course of L-ambisome or cryptococcal meningitis treatment can put this out of reach for many,” she told this news organization.
“Simplification that maintains the highest quality of care is an important component of the public health approach for HIV treatment and care,” she added.
Dr. Doherty could not comment on any possible changes to WHO recommendations, which are formulated by an independent guideline development group, but a spokesperson said that “WHO is preparing an updated review of the evidence for treating cryptococcal disease as a first step towards updating guidance.”
Conventional treatment toxicities
Cryptococcal meningitis is a leading cause of death in HIV, and the conventional treatment of amphotericin B deoxycholate, though less expensive than L-AmB, is more toxic, causing anemia, renal impairment, and electrolyte abnormalities, Dr. Lawrence explained
Having previously shown a single 10 mg/kg dose of L-AmB to be as effective as the longer regimen of 14 daily doses in terms of clearing cryptococcus from the cerebrospinal fluid, Dr. Lawrence and his colleagues conducted the phase 3 AMBITION-Cm trial to evaluate the effect on mortality, enrolling 844 patients in Botswana, Malawi, South Africa, Uganda, and Zimbabwe who were HIV-positive and had a first episode of cryptococcal meningitis.
Participants in the study were randomized to treatment either with single, high-dose L-AmB (10 mg/kg), combined with 14 days of flucytosine 100 mg/kg/day and fluconazole 1,200 mg/day or to a control group receiving 7 daily doses of AmB deoxycholate (1 mg/kg) plus 7 days of flucytosine 100 mg/kg/day, followed by 7 days of fluconazole 1,200 mg/day.
All patients were also provided with consolidation therapy of fluconazole 800 mg/day for eight weeks. Of the patients, 60.2% were male, their median age was 37, and their median CD4 count was 27 cells/mm3.
For the primary endpoint in the intention-to-treat analysis of 814 patients, the 10-week mortality rate in the single-dose L-AmB group was 24.82% (101 of 407) and 28.75% (117 of 407) in the control arm, for a difference (-3.93%) that was well within the pre-specified non-inferiority margin of 10%.
As expected, the safety measures were significantly improved with the single-dose of L-AmB: Rates of grade 3 or 4 adverse events within the initial 21 days of treatment in the single-dose L-AmB group were 50% versus 62.3% in the control group, and severe anemia occurred in just 13% of single-dose L-AmB participants, compared with 41% in the AmB deoxycholate control arm (both P < .001), Dr. Lawrence reported.
Furthermore, the average decline in hemoglobin over the first week was 0.3 g/dL in the single-dose L-AmB arm and 1.9 g/dL in the control arm, resulting in the need for more blood transfusions in the control arm (P < .001).
The impact on kidney function was also worse in the higher dose arm, with an average increase in creatinine over the first week of 20.2% in the L-AmB group versus 49.7% in the control group, while hypokalemia and thrombophlebitis were also more common with the higher dose group, Dr. Lawrence noted.
In the adjusted analysis, the single-dose L-AmB measures were in fact superior after adjusting for factors including research site, age, sex, baseline Glasgow Coma Scale, CD4 count, CSF cryptococcal colony-forming units/mL, antiretroviral therapy status, hemoglobin, and CSF opening pressure.
Mortality rate still high – but significantly reduced
The mortality rate of about 25% in the study after the treatment is still significantly higher than typically seen in high-income countries such as the United States, where HIV-associated cryptococcal meningitis is less common and associated with a mortality of roughly 10-15%, Dr. Lawrence noted.
The rate is nevertheless among the lowest mortality rates ever reported within a clinical trial conducted in resource-limited settings, he explained.
“These results are a step in the right direction and a significant improvement on the rates of 40% to 45% reported with two-week L-AmB-based regimens in African settings,” Dr. Lawrence underscored.
Higher cost — but potentially more cost-effective
With a higher cost than AmB deoxycholate, L-AmB’s utilization in resource-limited settings has been a challenge: A single vial of L-AmB ranges from $80 to $200, according to some reports, and while 14-day dosing requires as many as 42 vials of L-AmB, even a 7-day regimen still requires 21 vials.
In comparison, the single-dose L-AmB regimen only requires an average of 10 to 11 vials per patient, but the regimen’s higher safety could translate to far greater cost savings, Dr. Lawrence explained.
“While the AmBisome regimen is technically more expensive in terms of drugs, we expect it to be cost-effective or possibly cost-saving when taking into account that there is less toxicity, fewer blood tests, less transfusions, etc., and possibly shorter duration of hospital admission,” he said.
Cost, supply controversy: ‘Black fungus’-related demand
The drug’s cost — as well as supply issues — have meanwhile become even more of a problem as L-AmB has unexpectedly also become urgently needed in the treatment of mucormycosis in India and Nepal, where the otherwise rare fungal disease, commonly known as “black fungus,” has been increasingly affecting COVID-19 patients and survivors.
Gilead had previously announced in 2018 its intention to make L-AmB more widely available at a price of $16.25 per vial, but “implementation of this has been slow,” Dr. Lawrence said.
As a result, Gilead is facing heightened pressure to implement the lower prices – and also improve substantial supply issues, with Médecins Sans Frontières (Doctors Without Borders) and dozens of other global organizations issuing an open letter to Gilead and partner Viatris in June calling for immediate action to implement the lower price and improve supply of L-AmB.
In a company statement, Gilead responded, detailing its “commit[ment] to the non-profit pricing for the treatment of cryptococcal meningitis” and to efforts to improve the public health crisis in India.
For their part, Dr. Lawrence and his colleagues are working on producing more research on the issue.
“We hope that the conclusive results of the AMBITION trial will give a much needed push to implement this program,” he said.
“We are also currently completing the cost-effectiveness analysis of the study, which we hope will provide additional evidence to support widespread implementation of this regimen and highlight further the urgent need to broaden access to AmBisome and flucytosine,” he said.
The trial was supported by a grant through the European Developing Countries Clinical Trials Partnership (EDCTP), the Swedish International Development Cooperation Agency (SIDA) (TRIA2015-1092), and the Wellcome Trust / Medical Research Council (UK)/UKAID Joint Global Health Trials (MR/P006922/1. The AmBisome was donated by Gilead Sciences. Dr. Lawrence had no disclosures to report.
REPORTING FROM IAS 2021
Twice-a-year lenacapavir shows viral suppression in drug-resistant HIV at 26 weeks
With regulatory approval, lenacapavir could become the only HIV-1 treatment option given every 6 months.
“These data support the use of lenacapavir in patients with multidrug-resistant viruses, and according to its long half-life of two subcutaneous injections per year, [it] could help reduce pill burden,” first author Jean-Michel Molina, MD, PhD, professor of infectious diseases and head of the infectious diseases department at the Saint-Louis and Lariboisière Hospitals, Paris, said in an interview.
Presenting the updated findings from the phase 2/3 CAPELLA trial at the virtual annual meeting of the International AIDS Society conference, Dr. Molina underscored the need for longer-term treatments.
“These patients with multidrug resistances are usually those who have not been fully adherent to their regimen,” he said. “Being able to provide the drug, given every 6 months subcutaneously, provides an ideal treatment for overcoming resistance and lack of adherence.”
The study showed that, after 26 weeks, 81% of heavily treatment-experienced people with HIV in a randomized cohort who were treated with a subcutaneous injection of lenacapavir (927 mg) combined with an optimized background antiretroviral regimen achieved sustained virologic suppression, with an undetectable viral load (<50 copies/mL).
In addition, the lenacapavir-treated patients had a clinically meaningful mean increase in CD4 counts of 81 cells/mcL over the 26 weeks.
The drug was well tolerated, with no drug-related serious adverse events or adverse events leading to discontinuation. The most common adverse events were injection-site reactions, which occurred in 56% of participants, with most being mild or moderate.
Importantly, four participants developed emergent resistances to lenacapavir. One was suppressed with a change in the background regimen and two others were suppressed without a change in regimen.
“We know that these mutations affect viral fitness,” Dr. Molina said in an interview. “We need more studies to assess the real impact of these mutations.”
Dr. Molina noted that a phase 2 study is already underway to evaluate how a pairing of lenacapavir with fellow investigational long-acting drug islatravir (Merck) could offset the risk of developing resistances.
Asked by an audience member whether a two-drug regimen with something like islatravir is likely to successfully prevent resistances, Dr. Molina responded that “it’s too early to know what’s going to happen with [combinations], but these first results are really encouraging when you see the very high rate of being fully suppressed after 26 weeks. The efficacy that we’ve seen after [a previous 2-week analysis] is long lasting.”
Lenacapavir targets multiple viral stages
Unlike other antiviral drugs that target just a single stage of viral replication, lenacapavir takes aim at multiple steps in the viral life cycle, including capsid-mediated uptake of HIV-1 proviral DNA, virus assembly and release, and capsid core formation, Dr. Molina explained.
The CAPELLA trial included participants at research centers in North America, Europe, and Asia, with a median age of 52 years; 25% were female, 38% were Black, and their mean HIV-1 RNA (viral load) was 4.17 log copies/mL.
Overall, 72 patients were divided into two cohorts of 36 patients each, including a randomized and nonrandomized cohort. Dr. Molina primarily reported results from the randomized group.
In that group, patients received either a lead-in of oral lenacapavir (600 mg on day 1 and 2 and 300 mg on day 8) or placebo, in combination with patients’ current failing drug regimens in both groups.
At day 15, all participants were switched to the investigator-selected, optimized background treatment regimen, tailored according to patients’ drug-resistance profiles, and those in the lenacapavir group received the subcutaneous injection of lenacapavir; those in the placebo group were switched to the oral lead-in, followed by subcutaneous lenacapavir every 6 months.
Combined data that included six patients from the nonrandomized cohort showed that 79% of patients had a viral load of less than 50 copies/mL at week 26. The 81% viral suppression rate represented the randomized group (29 of 36).
International AIDS Society cochair Hendrik Streeck, MD, director of the Institute of Virology and Institute for HIV Research at the University Bonn (Germany), said a twice-a-year drug could possibly have profound benefits with a reduction in daily pill burden.
“What makes this an interesting drug is that it is long acting, so one can imagine it has the potential to treat individuals such as those who are not very adherent to the antiretroviral therapy, or who can’t easily access treatment, for example in resource-limited settings,” he said in an interview. “The option to treat patients for the next months in advance could be a very important next step.”
Further data from CALIBRATE
Additional data on lenacapavir from the phase 2 CALIBRATE study, presented in a separate session, further showed the drug, given orally or subcutaneously in combination with oral daily emtricitabine/tenofovir alafenamide, resulted in high rates of viral suppression among 94% of 157 treatment-naive patients after 28 weeks.
Commenting on the research, session moderator Alexandra Calmy, MD, PhD, of the HIV/AIDS unit and LIPO & Metabolism group, infectious diseases division, Geneva University Hospitals, noted the study offered “interesting data indeed” – with some caveats: “Why position a new drug class in naive patients [when] we already have good options, available for a large range of various populations?”
Dr. Calmy noted that, in general, lenacapavir “would certainly be an added value with an adapted 6-monthly companion drug.”
But she raised another key issue: “When will we have data on pregnancy that would allow lenacapavir to really be a game changer worldwide?”
The study was funded by Gilead Sciences. Dr. Molina reported receiving research funding from Gilead and being on advisory boards for Gilead, Merck, ViiV, and Janssen. Dr. Calmy and Dr. Streeck reported no relevant financial relationships.
With regulatory approval, lenacapavir could become the only HIV-1 treatment option given every 6 months.
“These data support the use of lenacapavir in patients with multidrug-resistant viruses, and according to its long half-life of two subcutaneous injections per year, [it] could help reduce pill burden,” first author Jean-Michel Molina, MD, PhD, professor of infectious diseases and head of the infectious diseases department at the Saint-Louis and Lariboisière Hospitals, Paris, said in an interview.
Presenting the updated findings from the phase 2/3 CAPELLA trial at the virtual annual meeting of the International AIDS Society conference, Dr. Molina underscored the need for longer-term treatments.
“These patients with multidrug resistances are usually those who have not been fully adherent to their regimen,” he said. “Being able to provide the drug, given every 6 months subcutaneously, provides an ideal treatment for overcoming resistance and lack of adherence.”
The study showed that, after 26 weeks, 81% of heavily treatment-experienced people with HIV in a randomized cohort who were treated with a subcutaneous injection of lenacapavir (927 mg) combined with an optimized background antiretroviral regimen achieved sustained virologic suppression, with an undetectable viral load (<50 copies/mL).
In addition, the lenacapavir-treated patients had a clinically meaningful mean increase in CD4 counts of 81 cells/mcL over the 26 weeks.
The drug was well tolerated, with no drug-related serious adverse events or adverse events leading to discontinuation. The most common adverse events were injection-site reactions, which occurred in 56% of participants, with most being mild or moderate.
Importantly, four participants developed emergent resistances to lenacapavir. One was suppressed with a change in the background regimen and two others were suppressed without a change in regimen.
“We know that these mutations affect viral fitness,” Dr. Molina said in an interview. “We need more studies to assess the real impact of these mutations.”
Dr. Molina noted that a phase 2 study is already underway to evaluate how a pairing of lenacapavir with fellow investigational long-acting drug islatravir (Merck) could offset the risk of developing resistances.
Asked by an audience member whether a two-drug regimen with something like islatravir is likely to successfully prevent resistances, Dr. Molina responded that “it’s too early to know what’s going to happen with [combinations], but these first results are really encouraging when you see the very high rate of being fully suppressed after 26 weeks. The efficacy that we’ve seen after [a previous 2-week analysis] is long lasting.”
Lenacapavir targets multiple viral stages
Unlike other antiviral drugs that target just a single stage of viral replication, lenacapavir takes aim at multiple steps in the viral life cycle, including capsid-mediated uptake of HIV-1 proviral DNA, virus assembly and release, and capsid core formation, Dr. Molina explained.
The CAPELLA trial included participants at research centers in North America, Europe, and Asia, with a median age of 52 years; 25% were female, 38% were Black, and their mean HIV-1 RNA (viral load) was 4.17 log copies/mL.
Overall, 72 patients were divided into two cohorts of 36 patients each, including a randomized and nonrandomized cohort. Dr. Molina primarily reported results from the randomized group.
In that group, patients received either a lead-in of oral lenacapavir (600 mg on day 1 and 2 and 300 mg on day 8) or placebo, in combination with patients’ current failing drug regimens in both groups.
At day 15, all participants were switched to the investigator-selected, optimized background treatment regimen, tailored according to patients’ drug-resistance profiles, and those in the lenacapavir group received the subcutaneous injection of lenacapavir; those in the placebo group were switched to the oral lead-in, followed by subcutaneous lenacapavir every 6 months.
Combined data that included six patients from the nonrandomized cohort showed that 79% of patients had a viral load of less than 50 copies/mL at week 26. The 81% viral suppression rate represented the randomized group (29 of 36).
International AIDS Society cochair Hendrik Streeck, MD, director of the Institute of Virology and Institute for HIV Research at the University Bonn (Germany), said a twice-a-year drug could possibly have profound benefits with a reduction in daily pill burden.
“What makes this an interesting drug is that it is long acting, so one can imagine it has the potential to treat individuals such as those who are not very adherent to the antiretroviral therapy, or who can’t easily access treatment, for example in resource-limited settings,” he said in an interview. “The option to treat patients for the next months in advance could be a very important next step.”
Further data from CALIBRATE
Additional data on lenacapavir from the phase 2 CALIBRATE study, presented in a separate session, further showed the drug, given orally or subcutaneously in combination with oral daily emtricitabine/tenofovir alafenamide, resulted in high rates of viral suppression among 94% of 157 treatment-naive patients after 28 weeks.
Commenting on the research, session moderator Alexandra Calmy, MD, PhD, of the HIV/AIDS unit and LIPO & Metabolism group, infectious diseases division, Geneva University Hospitals, noted the study offered “interesting data indeed” – with some caveats: “Why position a new drug class in naive patients [when] we already have good options, available for a large range of various populations?”
Dr. Calmy noted that, in general, lenacapavir “would certainly be an added value with an adapted 6-monthly companion drug.”
But she raised another key issue: “When will we have data on pregnancy that would allow lenacapavir to really be a game changer worldwide?”
The study was funded by Gilead Sciences. Dr. Molina reported receiving research funding from Gilead and being on advisory boards for Gilead, Merck, ViiV, and Janssen. Dr. Calmy and Dr. Streeck reported no relevant financial relationships.
With regulatory approval, lenacapavir could become the only HIV-1 treatment option given every 6 months.
“These data support the use of lenacapavir in patients with multidrug-resistant viruses, and according to its long half-life of two subcutaneous injections per year, [it] could help reduce pill burden,” first author Jean-Michel Molina, MD, PhD, professor of infectious diseases and head of the infectious diseases department at the Saint-Louis and Lariboisière Hospitals, Paris, said in an interview.
Presenting the updated findings from the phase 2/3 CAPELLA trial at the virtual annual meeting of the International AIDS Society conference, Dr. Molina underscored the need for longer-term treatments.
“These patients with multidrug resistances are usually those who have not been fully adherent to their regimen,” he said. “Being able to provide the drug, given every 6 months subcutaneously, provides an ideal treatment for overcoming resistance and lack of adherence.”
The study showed that, after 26 weeks, 81% of heavily treatment-experienced people with HIV in a randomized cohort who were treated with a subcutaneous injection of lenacapavir (927 mg) combined with an optimized background antiretroviral regimen achieved sustained virologic suppression, with an undetectable viral load (<50 copies/mL).
In addition, the lenacapavir-treated patients had a clinically meaningful mean increase in CD4 counts of 81 cells/mcL over the 26 weeks.
The drug was well tolerated, with no drug-related serious adverse events or adverse events leading to discontinuation. The most common adverse events were injection-site reactions, which occurred in 56% of participants, with most being mild or moderate.
Importantly, four participants developed emergent resistances to lenacapavir. One was suppressed with a change in the background regimen and two others were suppressed without a change in regimen.
“We know that these mutations affect viral fitness,” Dr. Molina said in an interview. “We need more studies to assess the real impact of these mutations.”
Dr. Molina noted that a phase 2 study is already underway to evaluate how a pairing of lenacapavir with fellow investigational long-acting drug islatravir (Merck) could offset the risk of developing resistances.
Asked by an audience member whether a two-drug regimen with something like islatravir is likely to successfully prevent resistances, Dr. Molina responded that “it’s too early to know what’s going to happen with [combinations], but these first results are really encouraging when you see the very high rate of being fully suppressed after 26 weeks. The efficacy that we’ve seen after [a previous 2-week analysis] is long lasting.”
Lenacapavir targets multiple viral stages
Unlike other antiviral drugs that target just a single stage of viral replication, lenacapavir takes aim at multiple steps in the viral life cycle, including capsid-mediated uptake of HIV-1 proviral DNA, virus assembly and release, and capsid core formation, Dr. Molina explained.
The CAPELLA trial included participants at research centers in North America, Europe, and Asia, with a median age of 52 years; 25% were female, 38% were Black, and their mean HIV-1 RNA (viral load) was 4.17 log copies/mL.
Overall, 72 patients were divided into two cohorts of 36 patients each, including a randomized and nonrandomized cohort. Dr. Molina primarily reported results from the randomized group.
In that group, patients received either a lead-in of oral lenacapavir (600 mg on day 1 and 2 and 300 mg on day 8) or placebo, in combination with patients’ current failing drug regimens in both groups.
At day 15, all participants were switched to the investigator-selected, optimized background treatment regimen, tailored according to patients’ drug-resistance profiles, and those in the lenacapavir group received the subcutaneous injection of lenacapavir; those in the placebo group were switched to the oral lead-in, followed by subcutaneous lenacapavir every 6 months.
Combined data that included six patients from the nonrandomized cohort showed that 79% of patients had a viral load of less than 50 copies/mL at week 26. The 81% viral suppression rate represented the randomized group (29 of 36).
International AIDS Society cochair Hendrik Streeck, MD, director of the Institute of Virology and Institute for HIV Research at the University Bonn (Germany), said a twice-a-year drug could possibly have profound benefits with a reduction in daily pill burden.
“What makes this an interesting drug is that it is long acting, so one can imagine it has the potential to treat individuals such as those who are not very adherent to the antiretroviral therapy, or who can’t easily access treatment, for example in resource-limited settings,” he said in an interview. “The option to treat patients for the next months in advance could be a very important next step.”
Further data from CALIBRATE
Additional data on lenacapavir from the phase 2 CALIBRATE study, presented in a separate session, further showed the drug, given orally or subcutaneously in combination with oral daily emtricitabine/tenofovir alafenamide, resulted in high rates of viral suppression among 94% of 157 treatment-naive patients after 28 weeks.
Commenting on the research, session moderator Alexandra Calmy, MD, PhD, of the HIV/AIDS unit and LIPO & Metabolism group, infectious diseases division, Geneva University Hospitals, noted the study offered “interesting data indeed” – with some caveats: “Why position a new drug class in naive patients [when] we already have good options, available for a large range of various populations?”
Dr. Calmy noted that, in general, lenacapavir “would certainly be an added value with an adapted 6-monthly companion drug.”
But she raised another key issue: “When will we have data on pregnancy that would allow lenacapavir to really be a game changer worldwide?”
The study was funded by Gilead Sciences. Dr. Molina reported receiving research funding from Gilead and being on advisory boards for Gilead, Merck, ViiV, and Janssen. Dr. Calmy and Dr. Streeck reported no relevant financial relationships.
FROM IAS 2021
Resistant TB: Adjustments to BPaL regimen reduce AEs, not efficacy
Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.
“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.
As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.
However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.
Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.
Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.
“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.
Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.
“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.
Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.
“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
ZeNix trial
The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.
All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.
The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).
Percentages of patients with HIV were equal among the four groups, at about 20% each.
The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.
With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.
Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.
Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.
On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
Findings represent ‘great news’ in addressing concerns
Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.
“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.
“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”
The inclusion of patients with HIV was essential in the trial, he noted.
“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.
“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”
The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.
This article was updated 7/21/21.
Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.
“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.
As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.
However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.
Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.
Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.
“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.
Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.
“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.
Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.
“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
ZeNix trial
The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.
All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.
The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).
Percentages of patients with HIV were equal among the four groups, at about 20% each.
The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.
With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.
Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.
Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.
On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
Findings represent ‘great news’ in addressing concerns
Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.
“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.
“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”
The inclusion of patients with HIV was essential in the trial, he noted.
“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.
“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”
The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.
This article was updated 7/21/21.
Lower doses of linezolid in the BPaL drug regimen (bedaquiline, pretomanid, and linezolid) significantly reduce the adverse events associated with the treatment for patients with highly drug-resistant tuberculosis (TB) without compromising its high efficacy, new research shows.
“The ZeNix trial shows that reduced doses and/or shorter durations of linezolid appear to have high efficacy and improved safety,” said first author Francesca Conradie, MB, BCh, of the clinical HIV research unit, faculty of health sciences, University of Witwatersrand, Johannesburg, South Africa, in presenting the findings at the virtual meeting of the International AIDS Society conference.
As recently reported in the pivotal Nix-TB trial, the BPaL regimen yielded a 90% treatment success rate among people with highly drug-resistant forms of TB.
However, a 6-month regimen that included linezolid 1,200 mg resulted in toxic effects: 81% of patients in the study experienced peripheral neuropathy, and myelosuppression occurred in 48%. These effects often led to dose reductions or treatment interruption.
Adjustments in the dose of linezolid in the new ZeNix trial substantially reduced peripheral neuropathy to 13% and myelosuppression to 7%, with no significant reduction in the treatment response.
Importantly, the results were similar among patients with and those without HIV. This is of note because TB is the leading cause of death among patients with HIV.
“In the ZeNix trial, only 20% of patients were HIV infected, but in the [previous] Nix-TB trial, 30% were infected, so we have experience now in about 70 patients who were infected, and the outcomes were no different,” Dr. Conradie said in an interview.
Experts say the findings represent an important turn in the steep challenge of tackling highly resistant TB.
“In our opinion, these are exciting results that could change treatment guidelines for highly drug-resistant tuberculosis, with real benefits for the patients,” said Hendrik Streeck, MD, International AIDS Society cochair and director of the Institute of Virology and the Institute for HIV Research at the University Bonn (Germany), in a press conference.
Payam Nahid, MD, MPH, director of the Center for Tuberculosis at theUniversity of California, San Francisco, agreed.
“The results of this trial will impact global practices in treating drug-resistant TB as well as the design and conduct of future TB clinical trials,” Dr. Nahid said in an interview.
ZeNix trial
The phase 3 ZeNix trial included 181 patients with highly resistant TB in South Africa, Russia, Georgia, and Moldova. The mean age of the patients was 37 years; 67.4% were men, 63.5% were White, and 19.9% were HIV positive.
All patients were treated for 6 months with bedaquiline 200 mg daily for 8 weeks followed by 100 mg daily for 18 weeks, as well as pretomanid 200 mg daily.
The patients were randomly assigned to receive one of four daily doses of linezolid: 1,200 mg for 6 months (the original dose from the Nix-TB trial; n = 45) or 2 months (n = 46), or 600 mg for 6 or 2 months (45 patients each).
Percentages of patients with HIV were equal among the four groups, at about 20% each.
The primary outcomes – resolution of clinical disease and a negative culture status after 6 months – were observed across all linezolid dose groups. The success rate was 93% for those receiving 1,200 mg for 6 months, 89% for those receiving 1,200 mg for 2 months, 91% for those receiving 600 mg for 6 months, and 84% for those receiving 600 mg for 2 months.
With regard to the key adverse events of peripheral neuropathy and myelosuppression, manifested as anemia, the highest rates were among those who received linezolid 1,200 mg for 6 month, at 38% and 22%, respectively, compared with 24% and 17.4% among those who received 1,200 mg for 2 months, 24% and 2% among those who received 600 mg for 6 months, and 13% and 6.7% among those who received 600 mg for 2 months.
Four cases of optic neuropathy occurred among those who received 1,200 mg for 6 months; all cases resolved.
Patients who received 1,200 mg for 6 months required the highest number of linezolid dose modifications; 51% required changes that included reduction, interruption, or discontinuation, compared with 28% among those who received 1,200 mg for 2 months and 13% each in the other two groups.
On the basis of these results, “my personal opinion is that 600 mg at 6 months [of linezolid] is most likely the best strategy for the treatment of this highly resistant treatment population group,” Dr. Conradie told this news organization.
Findings represent ‘great news’ in addressing concerns
Dr. Nahid further commented that the results are highly encouraging in light of the ongoing concerns about the effects of linezolid in the BPaL regimen.
“This is great news,” he said. “The ZeNix trial addresses a key concern that providers and patients have had regarding the safety and tolerability of taking 6 months of linezolid at 1200 mg/d as part of the BPaL regimen.
“The findings that doses lower and durations shorter than the current 1,200 mg linezolid daily for 6 months will significantly expand the usability of the BPaL regimen worldwide.”
The inclusion of patients with HIV was essential in the trial, he noted.
“There are drug-drug interactions to be considered, among other factors that impact drug exposure,” Dr. Nahid said.
“Inclusion of patients living with HIV in this study means that any modifications to the BPaL regimen considered by the WHO [World Health Organization] and other policy decision makers will include data from this key population,” he said. “Of course, more data are needed on safety, tolerability, and efficacy on BPaL in general, and there are international cohorts and demonstration projects underway that will enhance our understanding of the regimen in HIV and in other special populations.”
The authors, Dr. Streeck, and Dr. Nahid have disclosed no relevant financial relationships.
This article was updated 7/21/21.
FROM IAS 2021
Levothyroxine overprescribing common, consistent over time
Most U.S. prescriptions for the thyroid hormone replacement drug levothyroxine are not appropriate for patients with mild subclinical hypothyroidism, a trend that has remained steady for a decade despite evidence showing no significant benefits for those patients, new research shows.
“These results suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care,” wrote the authors of the study published in JAMA Internal Medicine.
“There have been previous reports of increased levothyroxine overuse in the U.S., but this is the first paper to describe the nature of the drivers of the overuse,” first author Juan P. Brito, MD, of the division of endocrinology, diabetes, metabolism and nutrition, department of internal medicine, Mayo Clinic, Rochester, Minn., said in an interview.
The findings underscore the need to improve awareness of the ongoing overuse, said the authors of an accompanying editorial.
“We hope [this study] resonates as a call to action for clinicians to stop treating patients with mild subclinical hypothyroidism,” they wrote.
Only 8% of those receiving levothyroxine had overt hypothyroidism
For the study, Dr. Brito and colleagues analyzed data of adults enrolled in Medicare Advantage who filled levothyroxine prescriptions between January 2008 and December 2018 and had thyrotropin levels measured within 3 months prior to the prescription. Patients with a history of thyroid surgery, thyroid cancer, central hypothyroidism, or who were pregnant, were excluded from the study.
In the 110,842 patients who started levothyroxine during the study period, there were no significant changes in median thyrotropin levels at the time of treatment initiation, with a median level in 2008 of 5.8 mIU/L and a level in 2018 of 5.3 mIU/L (P = .79).
In a subanalysis of 58,706 patients for whom thyrotropin as well as free thyroxine (FT4 or T4) levels were available – which allowed for the determination of the level of hypothyroidism – levothyroxine was initiated for overt hypothyroidism in only 8.4% of cases.
In as many as 61.0% of cases, patients had subclinical hypothyroidism, and in 30.5% of cases, patients had normal thyroid levels.
While the proportion of adults with overt hypothyroidism initiated on levothyroxine significantly increased over the 10 years (7.6% to 8.4%; P = .02), rates of those with subclinical hypothyroidism remained unchanged (59.3% to 65.7%; P = .36), as did the proportion with normal thyroid function (32.9% to 26.2%; P = .84).
A closer look at patients specifically with subclinical hypothyroidism showed there were also no changes in the proportion with mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT4 or T4) between the beginning and end of the study period (48.2% vs. 57.9%; P = .73). Rates of moderate subclinical hypothyroidism (thyrotropin level 10-19.9 mIU/L) were also similar (8.5% to 6.4%; P = .16).
No significant benefit, but ample undesirable effects
The authors underscore that levothyroxine has been shown time and again to offer no significant benefit to patients with subclinical hypothyroidism of any type, emphasized in a 2018 meta-analysis of 21 randomized, controlled trials.
“Frequent initiation of levothyroxine in these patients is at odds with evidence demonstrating no significant association of levothyroxine replacement with measures of health-related quality of life, thyroid-related symptoms, depressive symptoms, fatigue, or cognitive function,” they explained.
In addition to showing no benefit for subclinical hypothyroidism, levothyroxine is associated with a host of unwanted side effects, noted editorialists William K. Silverstein, MD, of Sunnybrook Health Sciences Centre, department of medicine, University of Toronto, and Deborah Grady, MD, of the department of medicine, University of California, San Francisco.
Some studies have shown a link between long-term levothyroxine therapy and an increased risk of cardiovascular disease, cardiac dysrhythmias, osteoporosis, and fractures, they explained.
In addition, unnecessary treatment “increases pill burden and costs, necessitates routine physician visits and blood work, and requires modification of daily routines so that patients can take medications on an empty stomach,” the editorialists wrote.
Importantly, evidence shows that once levothyroxine treatment for subclinical hypothyroidism is started, most patients will continue the therapy for life, they added.
The fact that levothyroxine is among the most commonly prescribed drugs in the United States, with about 7% of the population estimated to have an active prescription when overt hypothyroidism affects only about 0.2%-2% of the population, underscores the extent of levothyroxine overuse, Dr. Silverstein said in an interview.
“The really notable surprise was how pervasive inappropriate use of levothyroxine was,” he said. “The fact that only 8% of patients had a biochemical indication for treatment is striking.”
Potential solutions: ‘Shift the conversation’
In terms of potential solutions to the problem, Dr. Silverstein suggested laboratories change reference ranges so that only thyrotropin values greater than 10 mIU/L are reported as abnormal.
“Studies have shown that changing the thyrotropin reference range is associated with clinicians’ prescribing patterns,” he noted.
Dr. Brito agreed, noting that “there are many guidelines with different hypothyroidism thresholds, so we need to be more consistent about the message to clinicians.
“In addition, we have to come up with different approaches to symptoms that have nothing to do with levothyroxine,” Dr. Brito said.
“I try to explain to patients that it’s very unlikely that subclinical hypothyroidism would be driving significant symptoms like fatigue, weight gain, and hair loss,” Dr. Brito said. “So, one approach is to shift the conversation from how your thyroid is causing this to ‘how are we going to treat the symptoms?’ ”
The study was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Dr. Silverstein has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Most U.S. prescriptions for the thyroid hormone replacement drug levothyroxine are not appropriate for patients with mild subclinical hypothyroidism, a trend that has remained steady for a decade despite evidence showing no significant benefits for those patients, new research shows.
“These results suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care,” wrote the authors of the study published in JAMA Internal Medicine.
“There have been previous reports of increased levothyroxine overuse in the U.S., but this is the first paper to describe the nature of the drivers of the overuse,” first author Juan P. Brito, MD, of the division of endocrinology, diabetes, metabolism and nutrition, department of internal medicine, Mayo Clinic, Rochester, Minn., said in an interview.
The findings underscore the need to improve awareness of the ongoing overuse, said the authors of an accompanying editorial.
“We hope [this study] resonates as a call to action for clinicians to stop treating patients with mild subclinical hypothyroidism,” they wrote.
Only 8% of those receiving levothyroxine had overt hypothyroidism
For the study, Dr. Brito and colleagues analyzed data of adults enrolled in Medicare Advantage who filled levothyroxine prescriptions between January 2008 and December 2018 and had thyrotropin levels measured within 3 months prior to the prescription. Patients with a history of thyroid surgery, thyroid cancer, central hypothyroidism, or who were pregnant, were excluded from the study.
In the 110,842 patients who started levothyroxine during the study period, there were no significant changes in median thyrotropin levels at the time of treatment initiation, with a median level in 2008 of 5.8 mIU/L and a level in 2018 of 5.3 mIU/L (P = .79).
In a subanalysis of 58,706 patients for whom thyrotropin as well as free thyroxine (FT4 or T4) levels were available – which allowed for the determination of the level of hypothyroidism – levothyroxine was initiated for overt hypothyroidism in only 8.4% of cases.
In as many as 61.0% of cases, patients had subclinical hypothyroidism, and in 30.5% of cases, patients had normal thyroid levels.
While the proportion of adults with overt hypothyroidism initiated on levothyroxine significantly increased over the 10 years (7.6% to 8.4%; P = .02), rates of those with subclinical hypothyroidism remained unchanged (59.3% to 65.7%; P = .36), as did the proportion with normal thyroid function (32.9% to 26.2%; P = .84).
A closer look at patients specifically with subclinical hypothyroidism showed there were also no changes in the proportion with mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT4 or T4) between the beginning and end of the study period (48.2% vs. 57.9%; P = .73). Rates of moderate subclinical hypothyroidism (thyrotropin level 10-19.9 mIU/L) were also similar (8.5% to 6.4%; P = .16).
No significant benefit, but ample undesirable effects
The authors underscore that levothyroxine has been shown time and again to offer no significant benefit to patients with subclinical hypothyroidism of any type, emphasized in a 2018 meta-analysis of 21 randomized, controlled trials.
“Frequent initiation of levothyroxine in these patients is at odds with evidence demonstrating no significant association of levothyroxine replacement with measures of health-related quality of life, thyroid-related symptoms, depressive symptoms, fatigue, or cognitive function,” they explained.
In addition to showing no benefit for subclinical hypothyroidism, levothyroxine is associated with a host of unwanted side effects, noted editorialists William K. Silverstein, MD, of Sunnybrook Health Sciences Centre, department of medicine, University of Toronto, and Deborah Grady, MD, of the department of medicine, University of California, San Francisco.
Some studies have shown a link between long-term levothyroxine therapy and an increased risk of cardiovascular disease, cardiac dysrhythmias, osteoporosis, and fractures, they explained.
In addition, unnecessary treatment “increases pill burden and costs, necessitates routine physician visits and blood work, and requires modification of daily routines so that patients can take medications on an empty stomach,” the editorialists wrote.
Importantly, evidence shows that once levothyroxine treatment for subclinical hypothyroidism is started, most patients will continue the therapy for life, they added.
The fact that levothyroxine is among the most commonly prescribed drugs in the United States, with about 7% of the population estimated to have an active prescription when overt hypothyroidism affects only about 0.2%-2% of the population, underscores the extent of levothyroxine overuse, Dr. Silverstein said in an interview.
“The really notable surprise was how pervasive inappropriate use of levothyroxine was,” he said. “The fact that only 8% of patients had a biochemical indication for treatment is striking.”
Potential solutions: ‘Shift the conversation’
In terms of potential solutions to the problem, Dr. Silverstein suggested laboratories change reference ranges so that only thyrotropin values greater than 10 mIU/L are reported as abnormal.
“Studies have shown that changing the thyrotropin reference range is associated with clinicians’ prescribing patterns,” he noted.
Dr. Brito agreed, noting that “there are many guidelines with different hypothyroidism thresholds, so we need to be more consistent about the message to clinicians.
“In addition, we have to come up with different approaches to symptoms that have nothing to do with levothyroxine,” Dr. Brito said.
“I try to explain to patients that it’s very unlikely that subclinical hypothyroidism would be driving significant symptoms like fatigue, weight gain, and hair loss,” Dr. Brito said. “So, one approach is to shift the conversation from how your thyroid is causing this to ‘how are we going to treat the symptoms?’ ”
The study was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Dr. Silverstein has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Most U.S. prescriptions for the thyroid hormone replacement drug levothyroxine are not appropriate for patients with mild subclinical hypothyroidism, a trend that has remained steady for a decade despite evidence showing no significant benefits for those patients, new research shows.
“These results suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care,” wrote the authors of the study published in JAMA Internal Medicine.
“There have been previous reports of increased levothyroxine overuse in the U.S., but this is the first paper to describe the nature of the drivers of the overuse,” first author Juan P. Brito, MD, of the division of endocrinology, diabetes, metabolism and nutrition, department of internal medicine, Mayo Clinic, Rochester, Minn., said in an interview.
The findings underscore the need to improve awareness of the ongoing overuse, said the authors of an accompanying editorial.
“We hope [this study] resonates as a call to action for clinicians to stop treating patients with mild subclinical hypothyroidism,” they wrote.
Only 8% of those receiving levothyroxine had overt hypothyroidism
For the study, Dr. Brito and colleagues analyzed data of adults enrolled in Medicare Advantage who filled levothyroxine prescriptions between January 2008 and December 2018 and had thyrotropin levels measured within 3 months prior to the prescription. Patients with a history of thyroid surgery, thyroid cancer, central hypothyroidism, or who were pregnant, were excluded from the study.
In the 110,842 patients who started levothyroxine during the study period, there were no significant changes in median thyrotropin levels at the time of treatment initiation, with a median level in 2008 of 5.8 mIU/L and a level in 2018 of 5.3 mIU/L (P = .79).
In a subanalysis of 58,706 patients for whom thyrotropin as well as free thyroxine (FT4 or T4) levels were available – which allowed for the determination of the level of hypothyroidism – levothyroxine was initiated for overt hypothyroidism in only 8.4% of cases.
In as many as 61.0% of cases, patients had subclinical hypothyroidism, and in 30.5% of cases, patients had normal thyroid levels.
While the proportion of adults with overt hypothyroidism initiated on levothyroxine significantly increased over the 10 years (7.6% to 8.4%; P = .02), rates of those with subclinical hypothyroidism remained unchanged (59.3% to 65.7%; P = .36), as did the proportion with normal thyroid function (32.9% to 26.2%; P = .84).
A closer look at patients specifically with subclinical hypothyroidism showed there were also no changes in the proportion with mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT4 or T4) between the beginning and end of the study period (48.2% vs. 57.9%; P = .73). Rates of moderate subclinical hypothyroidism (thyrotropin level 10-19.9 mIU/L) were also similar (8.5% to 6.4%; P = .16).
No significant benefit, but ample undesirable effects
The authors underscore that levothyroxine has been shown time and again to offer no significant benefit to patients with subclinical hypothyroidism of any type, emphasized in a 2018 meta-analysis of 21 randomized, controlled trials.
“Frequent initiation of levothyroxine in these patients is at odds with evidence demonstrating no significant association of levothyroxine replacement with measures of health-related quality of life, thyroid-related symptoms, depressive symptoms, fatigue, or cognitive function,” they explained.
In addition to showing no benefit for subclinical hypothyroidism, levothyroxine is associated with a host of unwanted side effects, noted editorialists William K. Silverstein, MD, of Sunnybrook Health Sciences Centre, department of medicine, University of Toronto, and Deborah Grady, MD, of the department of medicine, University of California, San Francisco.
Some studies have shown a link between long-term levothyroxine therapy and an increased risk of cardiovascular disease, cardiac dysrhythmias, osteoporosis, and fractures, they explained.
In addition, unnecessary treatment “increases pill burden and costs, necessitates routine physician visits and blood work, and requires modification of daily routines so that patients can take medications on an empty stomach,” the editorialists wrote.
Importantly, evidence shows that once levothyroxine treatment for subclinical hypothyroidism is started, most patients will continue the therapy for life, they added.
The fact that levothyroxine is among the most commonly prescribed drugs in the United States, with about 7% of the population estimated to have an active prescription when overt hypothyroidism affects only about 0.2%-2% of the population, underscores the extent of levothyroxine overuse, Dr. Silverstein said in an interview.
“The really notable surprise was how pervasive inappropriate use of levothyroxine was,” he said. “The fact that only 8% of patients had a biochemical indication for treatment is striking.”
Potential solutions: ‘Shift the conversation’
In terms of potential solutions to the problem, Dr. Silverstein suggested laboratories change reference ranges so that only thyrotropin values greater than 10 mIU/L are reported as abnormal.
“Studies have shown that changing the thyrotropin reference range is associated with clinicians’ prescribing patterns,” he noted.
Dr. Brito agreed, noting that “there are many guidelines with different hypothyroidism thresholds, so we need to be more consistent about the message to clinicians.
“In addition, we have to come up with different approaches to symptoms that have nothing to do with levothyroxine,” Dr. Brito said.
“I try to explain to patients that it’s very unlikely that subclinical hypothyroidism would be driving significant symptoms like fatigue, weight gain, and hair loss,” Dr. Brito said. “So, one approach is to shift the conversation from how your thyroid is causing this to ‘how are we going to treat the symptoms?’ ”
The study was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Dr. Silverstein has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Reduced-intensity transplant benefits older patients with AML
Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.
“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.
Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.
Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”
“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.
Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.
HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.
However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.
To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.
Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.
In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.
In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.
In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.
The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.
In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).
In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).
Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).
Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).
In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.
An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).
Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).
The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.
They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).
However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.
“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.
“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.
“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.
In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.
“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.
“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.
Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.
“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.
Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.
Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”
“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.
Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.
HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.
However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.
To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.
Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.
In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.
In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.
In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.
The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.
In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).
In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).
Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).
Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).
In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.
An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).
Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).
The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.
They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).
However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.
“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.
“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.
“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.
In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.
“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.
“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.
Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.
“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.
Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.
Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”
“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.
Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.
HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.
However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.
To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.
Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.
In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.
In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.
In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.
The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.
In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).
In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).
Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).
Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).
In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.
An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).
Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).
The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.
They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).
However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.
“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.
“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.
“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.
In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.
“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.
“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.
Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
Obesity amplifies harmful effects of alcohol on the liver
Being overweight or having obesity significantly increases the risk for liver disease and the likelihood of dying from it compared with being of normal weight, regardless of level of alcohol consumption, new research shows.
"People in the overweight or obese range who drank were found to be at greater risk of liver diseases compared with participants within a healthy weight range who consumed alcohol at the same level," senior author Emmanuel Stamatakis, PhD, of the Charles Perkins Centre and the Faculty of Medicine and Health, Sydney, said in a press statement.
"Even for people who drank within alcohol guidelines, participants classified as obese were at over 50% greater risk of liver disease," he said.
"Obesity is an independent risk factor for steatosis, acute alcoholic hepatitis, and cirrhosis in alcoholic liver disease (ALD), which may increase the risk of mortality in ALD patients," the study's first author, Elif Inan-Eroglu, PhD, a postdoctoral research fellow at the Charles Perkins Centre, said in an interview.
Further prospective studies are needed to better understand the underlying mechanisms behind the association between alcohol consumption and liver disease across different adiposity levels, the authors say.
Meanwhile, the take-home message from the findings should be that "clinicians should consider the presence of overweight and obesity when they discuss defining safe alcohol levels for their patients, keeping in mind that there is no 'safe' level of alcohol," Dr. Inan-Eroglu said.
"Alcohol drinking guidelines need to acknowledge that two-thirds of the adult population are overweight or obese and consider specific recommendations for this majority population group," he said.
First and largest study of its kind
Obesity, well-known to be an independent risk factor for nonalcoholic fatty liver disease (NAFLD), is also known to worsen outcomes in ALD. And likewise, alcohol consumption, the cause of ALD, can promote obesity and therefore increase the risk of NAFLD.
Dr. Stamatakis and colleagues sought to evaluate the roles of the combined factors in terms of incidence and mortality in both ALD and NAFLD.
For the study, published online May 31 in the European Journal of Clinical Nutrition, they evaluated data from 465,437 participants in the U.K. Biobank. The study is said to be the first and largest of its kind.
In the cohort, a total of 1,090 liver disease deaths were recorded, including 230 deaths from ALD and 192 from NAFLD over an average follow-up of 10.5 years.
After a multivariate adjustment, the overall risk of ALD, NAFLD, and liver disease incidence and mortality were significantly higher in participants who were overweight or had obesity, compared with those of normal weight, at all levels of alcohol consumption.
For instance, among those with alcohol use exceeding guidelines, the risk of ALD was significantly increased in normal weight individuals versus never-drinkers (hazard ratio [HR], 5.38), and the risk was even higher among those who were also overweight or had obesity (HR, 8.58).
In terms of the risk of death related to ALD, among those reporting alcohol consumption above guidelines, the risk was nearly double among those who were overweight or had obesity (HR, 10.29) versus those with normal weight (HR, 5.84), when each group was compared to those drinking within guidelines.
Regarding NAFLD, consistent with evidence that low to moderate alcohol consumption is, in fact, linked to a reduced risk, those in the study who reported alcohol consumption within guidelines and normal weight did show a reduced risk of NAFLD compared with an index group of never-drinkers (HR, 0.85).
However, being overweight or having obesity increased the risk of NAFLD in those participants (HR, 1.51).
Furthermore, even those reporting alcohol consumption above guidelines who were of normal weight had a reduced risk of NAFLD compared with never drinkers of normal weight (HR, 0.89).
Regarding the risk of liver disease among those reporting alcohol consumption above guidelines compared with never-drinkers, the risk was again lower among those of normal weight versus those who were overweight or had obesity (HR, 0.95 vs. 1.52), as were the risks of mortality (HR, 1.24 vs. 2.20).
Overall, "we found evidence that being overweight/[having obesity] amplified the harmful effect of alcohol on the liver disease incidence and mortality," the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com
Being overweight or having obesity significantly increases the risk for liver disease and the likelihood of dying from it compared with being of normal weight, regardless of level of alcohol consumption, new research shows.
"People in the overweight or obese range who drank were found to be at greater risk of liver diseases compared with participants within a healthy weight range who consumed alcohol at the same level," senior author Emmanuel Stamatakis, PhD, of the Charles Perkins Centre and the Faculty of Medicine and Health, Sydney, said in a press statement.
"Even for people who drank within alcohol guidelines, participants classified as obese were at over 50% greater risk of liver disease," he said.
"Obesity is an independent risk factor for steatosis, acute alcoholic hepatitis, and cirrhosis in alcoholic liver disease (ALD), which may increase the risk of mortality in ALD patients," the study's first author, Elif Inan-Eroglu, PhD, a postdoctoral research fellow at the Charles Perkins Centre, said in an interview.
Further prospective studies are needed to better understand the underlying mechanisms behind the association between alcohol consumption and liver disease across different adiposity levels, the authors say.
Meanwhile, the take-home message from the findings should be that "clinicians should consider the presence of overweight and obesity when they discuss defining safe alcohol levels for their patients, keeping in mind that there is no 'safe' level of alcohol," Dr. Inan-Eroglu said.
"Alcohol drinking guidelines need to acknowledge that two-thirds of the adult population are overweight or obese and consider specific recommendations for this majority population group," he said.
First and largest study of its kind
Obesity, well-known to be an independent risk factor for nonalcoholic fatty liver disease (NAFLD), is also known to worsen outcomes in ALD. And likewise, alcohol consumption, the cause of ALD, can promote obesity and therefore increase the risk of NAFLD.
Dr. Stamatakis and colleagues sought to evaluate the roles of the combined factors in terms of incidence and mortality in both ALD and NAFLD.
For the study, published online May 31 in the European Journal of Clinical Nutrition, they evaluated data from 465,437 participants in the U.K. Biobank. The study is said to be the first and largest of its kind.
In the cohort, a total of 1,090 liver disease deaths were recorded, including 230 deaths from ALD and 192 from NAFLD over an average follow-up of 10.5 years.
After a multivariate adjustment, the overall risk of ALD, NAFLD, and liver disease incidence and mortality were significantly higher in participants who were overweight or had obesity, compared with those of normal weight, at all levels of alcohol consumption.
For instance, among those with alcohol use exceeding guidelines, the risk of ALD was significantly increased in normal weight individuals versus never-drinkers (hazard ratio [HR], 5.38), and the risk was even higher among those who were also overweight or had obesity (HR, 8.58).
In terms of the risk of death related to ALD, among those reporting alcohol consumption above guidelines, the risk was nearly double among those who were overweight or had obesity (HR, 10.29) versus those with normal weight (HR, 5.84), when each group was compared to those drinking within guidelines.
Regarding NAFLD, consistent with evidence that low to moderate alcohol consumption is, in fact, linked to a reduced risk, those in the study who reported alcohol consumption within guidelines and normal weight did show a reduced risk of NAFLD compared with an index group of never-drinkers (HR, 0.85).
However, being overweight or having obesity increased the risk of NAFLD in those participants (HR, 1.51).
Furthermore, even those reporting alcohol consumption above guidelines who were of normal weight had a reduced risk of NAFLD compared with never drinkers of normal weight (HR, 0.89).
Regarding the risk of liver disease among those reporting alcohol consumption above guidelines compared with never-drinkers, the risk was again lower among those of normal weight versus those who were overweight or had obesity (HR, 0.95 vs. 1.52), as were the risks of mortality (HR, 1.24 vs. 2.20).
Overall, "we found evidence that being overweight/[having obesity] amplified the harmful effect of alcohol on the liver disease incidence and mortality," the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com
Being overweight or having obesity significantly increases the risk for liver disease and the likelihood of dying from it compared with being of normal weight, regardless of level of alcohol consumption, new research shows.
"People in the overweight or obese range who drank were found to be at greater risk of liver diseases compared with participants within a healthy weight range who consumed alcohol at the same level," senior author Emmanuel Stamatakis, PhD, of the Charles Perkins Centre and the Faculty of Medicine and Health, Sydney, said in a press statement.
"Even for people who drank within alcohol guidelines, participants classified as obese were at over 50% greater risk of liver disease," he said.
"Obesity is an independent risk factor for steatosis, acute alcoholic hepatitis, and cirrhosis in alcoholic liver disease (ALD), which may increase the risk of mortality in ALD patients," the study's first author, Elif Inan-Eroglu, PhD, a postdoctoral research fellow at the Charles Perkins Centre, said in an interview.
Further prospective studies are needed to better understand the underlying mechanisms behind the association between alcohol consumption and liver disease across different adiposity levels, the authors say.
Meanwhile, the take-home message from the findings should be that "clinicians should consider the presence of overweight and obesity when they discuss defining safe alcohol levels for their patients, keeping in mind that there is no 'safe' level of alcohol," Dr. Inan-Eroglu said.
"Alcohol drinking guidelines need to acknowledge that two-thirds of the adult population are overweight or obese and consider specific recommendations for this majority population group," he said.
First and largest study of its kind
Obesity, well-known to be an independent risk factor for nonalcoholic fatty liver disease (NAFLD), is also known to worsen outcomes in ALD. And likewise, alcohol consumption, the cause of ALD, can promote obesity and therefore increase the risk of NAFLD.
Dr. Stamatakis and colleagues sought to evaluate the roles of the combined factors in terms of incidence and mortality in both ALD and NAFLD.
For the study, published online May 31 in the European Journal of Clinical Nutrition, they evaluated data from 465,437 participants in the U.K. Biobank. The study is said to be the first and largest of its kind.
In the cohort, a total of 1,090 liver disease deaths were recorded, including 230 deaths from ALD and 192 from NAFLD over an average follow-up of 10.5 years.
After a multivariate adjustment, the overall risk of ALD, NAFLD, and liver disease incidence and mortality were significantly higher in participants who were overweight or had obesity, compared with those of normal weight, at all levels of alcohol consumption.
For instance, among those with alcohol use exceeding guidelines, the risk of ALD was significantly increased in normal weight individuals versus never-drinkers (hazard ratio [HR], 5.38), and the risk was even higher among those who were also overweight or had obesity (HR, 8.58).
In terms of the risk of death related to ALD, among those reporting alcohol consumption above guidelines, the risk was nearly double among those who were overweight or had obesity (HR, 10.29) versus those with normal weight (HR, 5.84), when each group was compared to those drinking within guidelines.
Regarding NAFLD, consistent with evidence that low to moderate alcohol consumption is, in fact, linked to a reduced risk, those in the study who reported alcohol consumption within guidelines and normal weight did show a reduced risk of NAFLD compared with an index group of never-drinkers (HR, 0.85).
However, being overweight or having obesity increased the risk of NAFLD in those participants (HR, 1.51).
Furthermore, even those reporting alcohol consumption above guidelines who were of normal weight had a reduced risk of NAFLD compared with never drinkers of normal weight (HR, 0.89).
Regarding the risk of liver disease among those reporting alcohol consumption above guidelines compared with never-drinkers, the risk was again lower among those of normal weight versus those who were overweight or had obesity (HR, 0.95 vs. 1.52), as were the risks of mortality (HR, 1.24 vs. 2.20).
Overall, "we found evidence that being overweight/[having obesity] amplified the harmful effect of alcohol on the liver disease incidence and mortality," the authors conclude.
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com
Osteoporosis linked to increased risk of hearing loss
Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.
The use of bisphosphonate therapy did not alter the risk, the researchers found.
“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.
“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.
“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
Participants were from the nurses’ health study and NHS II
With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.
In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.
Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.
After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).
And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).
No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.
Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).
However, the increased risk of hearing loss was not observed with hip fracture.
“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.
“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
Audiometric subanalysis
In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.
However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.
The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.
In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.
“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
Mechanisms: Bone loss may extend to ear structures
In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.
“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”
They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.
Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.
Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.
In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.
“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.
“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”
The study received support from the National Institutes of Health.
A version of this article first appeared on Medscape.com.
Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.
The use of bisphosphonate therapy did not alter the risk, the researchers found.
“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.
“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.
“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
Participants were from the nurses’ health study and NHS II
With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.
In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.
Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.
After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).
And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).
No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.
Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).
However, the increased risk of hearing loss was not observed with hip fracture.
“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.
“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
Audiometric subanalysis
In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.
However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.
The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.
In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.
“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
Mechanisms: Bone loss may extend to ear structures
In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.
“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”
They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.
Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.
Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.
In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.
“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.
“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”
The study received support from the National Institutes of Health.
A version of this article first appeared on Medscape.com.
Women with osteoporosis, low bone density, or a previous vertebral fracture show significant increases in the risk of hearing loss compared to those without osteoporosis, according to a new study with more than 3 decades of follow-up.
The use of bisphosphonate therapy did not alter the risk, the researchers found.
“To the best of our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures, and risk of hearing loss,” reported Sharon Curhan, MD, and colleagues in research published online in the Journal of the American Geriatric Society.
“In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or low bone density was independently associated with higher risk of incident moderate or worse hearing loss,” the authors wrote.
“The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates,” they added.
Participants were from the nurses’ health study and NHS II
With recent research suggesting a potential link between bisphosphonate use and prevention of noise-induced hearing loss in mice, Dr. Curhan, of the Channing Division of Network Medicine at Brigham and Women’s Hospital, Boston, and colleagues turned to the large longitudinal cohorts of the Nurses’ Health Study (NHS), conducted from 1982 to 2016, and the Nurses’ Health Study II (NHS II), from 1995 to 2017.
In total, the primary analysis included 60,821 women in the NHS and 83,078 in the NHS II.
Women in the NHS were aged 36-61 years at baseline and 70-95 years at the end of follow-up, while in the NHS II, women were aged 31-48 years at baseline and 53-70 years at the end of follow-up.
After multivariate adjustment for key factors including age, race/ethnicity, oral hormone use, and a variety of other factors, women in the NHS with osteoporosis had an increased risk of moderate or worse hearing loss, as self-reported every 2 years, compared to those without osteoporosis (relative risk, 1.14; 95% confidence interval, 1.09-1.19).
And in the NHS II, which also included data on low bone density, the risk of self-reported hearing loss was higher among those with osteoporosis or low bone density (RR, 1.30; 95% CI, 1.21-1.40).
No significant differences were observed in hearing loss risk based on whether women were treated with bisphosphonates, with the mean duration of use of the medication being 5.8 years in the NHS and 3.4 years in the NHS II.
Those who sustained a vertebral fracture also had a higher risk of hearing loss in both studies (NHS: RR, 1.31; NHS II: RR, 1.39).
However, the increased risk of hearing loss was not observed with hip fracture.
“Our findings of up to a 40% higher risk among women with vertebral fracture, but not hip fracture, were intriguing and merit further study,” the authors noted.
“The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss,” they added.
Audiometric subanalysis
In an analysis of a subcohort of 3,749 women looking at audiometric thresholds for a more precise measure of hearing loss, women with osteoporosis or low bone density continued to show significantly worse hearing loss when treated with bisphosphonates compared to those without osteoporosis or low bone density.
However, there were no significant hearing loss differences among those with osteoporosis who did not take bisphosphonates versus those without osteoporosis.
The authors speculate that the use of bisphosphonates could have been indicative of more severe osteoporosis, hence the poorer audiometric thresholds.
In an interview, Dr. Curhan said the details of bisphosphonate use, such as type and duration, and their role in hearing loss should be further evaluated.
“Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose, and timing of bisphosphonate administration,” she observed. “This is an important question for further study.”
Mechanisms: Bone loss may extend to ear structures
In terms of the mechanisms linking osteoporosis itself to hearing loss, the authors noted that bone loss, in addition to compromising more prominent skeletal sites, could logically extend to bone-related structures in the ear.
“Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7,” they explained. “Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule, and the middle ear ossicles.”
They noted that hearing loss has been linked to other pathologic bone disorders, including otosclerosis and Paget disease.
Furthermore, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism, which can lead to hearing loss.
Looking ahead, Dr. Curhan and colleagues plan to further examine whether calcium and vitamin D, which are associated with the prevention of osteoporosis, have a role in preventing hearing loss.
In the meantime, the findings underscore that clinicians treating patients with osteoporosis should routinely check patients’ hearing, Dr. Curhan said.
“Undetected and untreated hearing loss can adversely impact social interactions, physical and mental well-being, and daily life,” she said.
“Early detection of hearing loss offers greater opportunity for successful management and to learn strategies for rehabilitation and prevention of further progression.”
The study received support from the National Institutes of Health.
A version of this article first appeared on Medscape.com.
Sardines linked to reduced type 2 diabetes risk
Older people with prediabetes who followed a diet rich in sardines for 1 year show significant reductions in risk of developing type 2 diabetes compared with those placed on a similarly healthy diet but without the sardines, results from a new randomized trial show.
“A 1-year, sardine-enriched type 2 diabetes-preventive diet in an elderly population with prediabetes exerts a greater protective effect against developing type 2 diabetes and cardiovascular events, by improving anthropometric parameters, blood chemistry profile, lipid composition in erythrocytes membranes, and metabolomics data,” report the authors in research published in Clinical Nutrition by Diana Díaz-Rizzolo, PhD, of the Hospital Clinic of Barcelona, Spain, and colleagues.
While cardiovascular and other health benefits of unsaturated fats in oily fish are well-established and are a key component in diets such as the highly recommended Mediterranean diet, the authors note that the consumption of sardines for the prevention of type 2 diabetes has not previously been studied.
In addition to being rich in healthy omega-3 fatty acids, sardines have high concentrations of taurine – approximately 147 mg per 100 g serving – which, depending on the sardine species, is believed to have hypoglycemic, antioxidant, and anti-inflammatory benefits, the authors note.
Participants advised to consume the whole sardine, bones and all
To evaluate the effects, researchers enrolled 152 patients aged 65 and older who had been diagnosed with prediabetes (blood glucose levels between 100-124 mg/dL) and placed them all on a nutritional program to reduce the risk of diabetes for 1 year.
In addition, about half (n = 75) were also instructed to consume 200 g of canned sardines in olive oil per week, in 100 g servings consumed twice per week.
Those participants were recommended to consume the entire sardine, without removal of bones, due to their rich content of calcium and vitamin D. They were also provided with recipes that used canned sardines.
At 1 year, the percentage of participants classified as being at a very high risk of type 2 diabetes, assessed by the Finnish Diabetes Risk Score (FINDRISC), compared with baseline, had declined to a much greater degree in the sardine consumption group (37% at baseline vs. 8% at 1 year) compared with those in the control group, who only consumed the nutritional diet (27% vs. 22%) (P = .021).
In addition, those in the sardine group had greater increases in healthy HDL cholesterol and the glucose-regulating protein hormone adiponectin, with decreases in triglycerides compared with the nonsardine group (all P < .005).
Furthermore, the sardine consumption group had a greater decrease in insulin resistance, assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR; P = .032).
Sardines are cheap and reduce blood pressure too
“Not only are sardines reasonably priced and easy to find, but they are safe and help to prevent the onset of type 2 diabetes,” said Dr. Díaz-Rizzolo in a press statement.
Those in the sardine group also showed significant decreases in systolic blood pressure (P = .014) and diastolic blood pressure (P = .020) versus baseline, while no significant changes were observed in the control group. The authors suggest that sardines’ rich taurine concentrations could play a role in those effects.
“Previously, only lean fish consumption had demonstrated an improvement in blood pressure, not fatty fish consumption, perhaps because the species studied excluded those with a higher taurine content such as sardines,” they speculate.
In addition to showing improvements in levels of taurine, those in the sardine group also showed increases in nutrients that have been linked to health benefits, including omega-3 EPA and DHA, vitamin D, and fluorine (all P < .05).
The authors note that the increases could be attributed to sardines’ rich concentration of those nutrients, as well as to the olive oil that is present in the sardine can.
Some benefits seen in both groups
The patients in the study were a mean age of 71 and had been in a prediabetic state for an average of 4.8 years at the beginning of the study. They were 55% male and there were no other significant differences in characteristics between the groups.
While the conversion from being prediabetic to type 2 diabetes in the adult population has been reported to be about 10.6%, and the risk has been observed to be even higher in the 65 and older population, rates were lower than that in both groups.
“At the end of our 1-year study, we observed a [rate of] new-onset type 2 diabetes of 2.7% and 5.2% in the sardine group and control group, respectively,” the authors note. They add the differences were not statistically significant.
Both the sardine consumption and control groups showed significant reductions in A1c versus baseline (P = .011 and P = .010, respectively), as well as significant reductions in glucose fasting concentrations (P = .020 and P = .040, respectively).
And while the sardine group showed greater improvements in HDL versus the control group (P = .045), only the control group showed a significant decrease in total cholesterol versus baseline (P = .032).
Both groups showed improvements in the management of body weight, body mass index, and waist and hip circumference, in addition to improvement in body composition – despite no physical activity components in the programs, the authors note.
“This is probably because both groups followed the same base type 2 diabetes-preventive diet, with the one exception of sardine supplementation, and, although they did not modify their physical activity, both groups reduced their daily caloric intake through food,” the authors note.
The possibility of reducing diabetes risk through dietary changes as opposed to weight loss is especially important in the older population, the authors note, as some studies suggest a link between weight loss in the elderly and an increased risk of mortality.
In a second phase of the study, the researchers say they are evaluating the effect of sardines on the intestinal microbiota, “since it affects the regulation of many biological processes, and we need to understand if they have played a part in this protective effect against type 2 diabetes,” Dr. Díaz-Rizzolo concluded.
The study was funded by RecerCaixa 2013. The authors report that “no industry sponsorship was received for this work that could have influenced its outcome.”
A version of this article first appeared on Medscape.com.
Older people with prediabetes who followed a diet rich in sardines for 1 year show significant reductions in risk of developing type 2 diabetes compared with those placed on a similarly healthy diet but without the sardines, results from a new randomized trial show.
“A 1-year, sardine-enriched type 2 diabetes-preventive diet in an elderly population with prediabetes exerts a greater protective effect against developing type 2 diabetes and cardiovascular events, by improving anthropometric parameters, blood chemistry profile, lipid composition in erythrocytes membranes, and metabolomics data,” report the authors in research published in Clinical Nutrition by Diana Díaz-Rizzolo, PhD, of the Hospital Clinic of Barcelona, Spain, and colleagues.
While cardiovascular and other health benefits of unsaturated fats in oily fish are well-established and are a key component in diets such as the highly recommended Mediterranean diet, the authors note that the consumption of sardines for the prevention of type 2 diabetes has not previously been studied.
In addition to being rich in healthy omega-3 fatty acids, sardines have high concentrations of taurine – approximately 147 mg per 100 g serving – which, depending on the sardine species, is believed to have hypoglycemic, antioxidant, and anti-inflammatory benefits, the authors note.
Participants advised to consume the whole sardine, bones and all
To evaluate the effects, researchers enrolled 152 patients aged 65 and older who had been diagnosed with prediabetes (blood glucose levels between 100-124 mg/dL) and placed them all on a nutritional program to reduce the risk of diabetes for 1 year.
In addition, about half (n = 75) were also instructed to consume 200 g of canned sardines in olive oil per week, in 100 g servings consumed twice per week.
Those participants were recommended to consume the entire sardine, without removal of bones, due to their rich content of calcium and vitamin D. They were also provided with recipes that used canned sardines.
At 1 year, the percentage of participants classified as being at a very high risk of type 2 diabetes, assessed by the Finnish Diabetes Risk Score (FINDRISC), compared with baseline, had declined to a much greater degree in the sardine consumption group (37% at baseline vs. 8% at 1 year) compared with those in the control group, who only consumed the nutritional diet (27% vs. 22%) (P = .021).
In addition, those in the sardine group had greater increases in healthy HDL cholesterol and the glucose-regulating protein hormone adiponectin, with decreases in triglycerides compared with the nonsardine group (all P < .005).
Furthermore, the sardine consumption group had a greater decrease in insulin resistance, assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR; P = .032).
Sardines are cheap and reduce blood pressure too
“Not only are sardines reasonably priced and easy to find, but they are safe and help to prevent the onset of type 2 diabetes,” said Dr. Díaz-Rizzolo in a press statement.
Those in the sardine group also showed significant decreases in systolic blood pressure (P = .014) and diastolic blood pressure (P = .020) versus baseline, while no significant changes were observed in the control group. The authors suggest that sardines’ rich taurine concentrations could play a role in those effects.
“Previously, only lean fish consumption had demonstrated an improvement in blood pressure, not fatty fish consumption, perhaps because the species studied excluded those with a higher taurine content such as sardines,” they speculate.
In addition to showing improvements in levels of taurine, those in the sardine group also showed increases in nutrients that have been linked to health benefits, including omega-3 EPA and DHA, vitamin D, and fluorine (all P < .05).
The authors note that the increases could be attributed to sardines’ rich concentration of those nutrients, as well as to the olive oil that is present in the sardine can.
Some benefits seen in both groups
The patients in the study were a mean age of 71 and had been in a prediabetic state for an average of 4.8 years at the beginning of the study. They were 55% male and there were no other significant differences in characteristics between the groups.
While the conversion from being prediabetic to type 2 diabetes in the adult population has been reported to be about 10.6%, and the risk has been observed to be even higher in the 65 and older population, rates were lower than that in both groups.
“At the end of our 1-year study, we observed a [rate of] new-onset type 2 diabetes of 2.7% and 5.2% in the sardine group and control group, respectively,” the authors note. They add the differences were not statistically significant.
Both the sardine consumption and control groups showed significant reductions in A1c versus baseline (P = .011 and P = .010, respectively), as well as significant reductions in glucose fasting concentrations (P = .020 and P = .040, respectively).
And while the sardine group showed greater improvements in HDL versus the control group (P = .045), only the control group showed a significant decrease in total cholesterol versus baseline (P = .032).
Both groups showed improvements in the management of body weight, body mass index, and waist and hip circumference, in addition to improvement in body composition – despite no physical activity components in the programs, the authors note.
“This is probably because both groups followed the same base type 2 diabetes-preventive diet, with the one exception of sardine supplementation, and, although they did not modify their physical activity, both groups reduced their daily caloric intake through food,” the authors note.
The possibility of reducing diabetes risk through dietary changes as opposed to weight loss is especially important in the older population, the authors note, as some studies suggest a link between weight loss in the elderly and an increased risk of mortality.
In a second phase of the study, the researchers say they are evaluating the effect of sardines on the intestinal microbiota, “since it affects the regulation of many biological processes, and we need to understand if they have played a part in this protective effect against type 2 diabetes,” Dr. Díaz-Rizzolo concluded.
The study was funded by RecerCaixa 2013. The authors report that “no industry sponsorship was received for this work that could have influenced its outcome.”
A version of this article first appeared on Medscape.com.
Older people with prediabetes who followed a diet rich in sardines for 1 year show significant reductions in risk of developing type 2 diabetes compared with those placed on a similarly healthy diet but without the sardines, results from a new randomized trial show.
“A 1-year, sardine-enriched type 2 diabetes-preventive diet in an elderly population with prediabetes exerts a greater protective effect against developing type 2 diabetes and cardiovascular events, by improving anthropometric parameters, blood chemistry profile, lipid composition in erythrocytes membranes, and metabolomics data,” report the authors in research published in Clinical Nutrition by Diana Díaz-Rizzolo, PhD, of the Hospital Clinic of Barcelona, Spain, and colleagues.
While cardiovascular and other health benefits of unsaturated fats in oily fish are well-established and are a key component in diets such as the highly recommended Mediterranean diet, the authors note that the consumption of sardines for the prevention of type 2 diabetes has not previously been studied.
In addition to being rich in healthy omega-3 fatty acids, sardines have high concentrations of taurine – approximately 147 mg per 100 g serving – which, depending on the sardine species, is believed to have hypoglycemic, antioxidant, and anti-inflammatory benefits, the authors note.
Participants advised to consume the whole sardine, bones and all
To evaluate the effects, researchers enrolled 152 patients aged 65 and older who had been diagnosed with prediabetes (blood glucose levels between 100-124 mg/dL) and placed them all on a nutritional program to reduce the risk of diabetes for 1 year.
In addition, about half (n = 75) were also instructed to consume 200 g of canned sardines in olive oil per week, in 100 g servings consumed twice per week.
Those participants were recommended to consume the entire sardine, without removal of bones, due to their rich content of calcium and vitamin D. They were also provided with recipes that used canned sardines.
At 1 year, the percentage of participants classified as being at a very high risk of type 2 diabetes, assessed by the Finnish Diabetes Risk Score (FINDRISC), compared with baseline, had declined to a much greater degree in the sardine consumption group (37% at baseline vs. 8% at 1 year) compared with those in the control group, who only consumed the nutritional diet (27% vs. 22%) (P = .021).
In addition, those in the sardine group had greater increases in healthy HDL cholesterol and the glucose-regulating protein hormone adiponectin, with decreases in triglycerides compared with the nonsardine group (all P < .005).
Furthermore, the sardine consumption group had a greater decrease in insulin resistance, assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR; P = .032).
Sardines are cheap and reduce blood pressure too
“Not only are sardines reasonably priced and easy to find, but they are safe and help to prevent the onset of type 2 diabetes,” said Dr. Díaz-Rizzolo in a press statement.
Those in the sardine group also showed significant decreases in systolic blood pressure (P = .014) and diastolic blood pressure (P = .020) versus baseline, while no significant changes were observed in the control group. The authors suggest that sardines’ rich taurine concentrations could play a role in those effects.
“Previously, only lean fish consumption had demonstrated an improvement in blood pressure, not fatty fish consumption, perhaps because the species studied excluded those with a higher taurine content such as sardines,” they speculate.
In addition to showing improvements in levels of taurine, those in the sardine group also showed increases in nutrients that have been linked to health benefits, including omega-3 EPA and DHA, vitamin D, and fluorine (all P < .05).
The authors note that the increases could be attributed to sardines’ rich concentration of those nutrients, as well as to the olive oil that is present in the sardine can.
Some benefits seen in both groups
The patients in the study were a mean age of 71 and had been in a prediabetic state for an average of 4.8 years at the beginning of the study. They were 55% male and there were no other significant differences in characteristics between the groups.
While the conversion from being prediabetic to type 2 diabetes in the adult population has been reported to be about 10.6%, and the risk has been observed to be even higher in the 65 and older population, rates were lower than that in both groups.
“At the end of our 1-year study, we observed a [rate of] new-onset type 2 diabetes of 2.7% and 5.2% in the sardine group and control group, respectively,” the authors note. They add the differences were not statistically significant.
Both the sardine consumption and control groups showed significant reductions in A1c versus baseline (P = .011 and P = .010, respectively), as well as significant reductions in glucose fasting concentrations (P = .020 and P = .040, respectively).
And while the sardine group showed greater improvements in HDL versus the control group (P = .045), only the control group showed a significant decrease in total cholesterol versus baseline (P = .032).
Both groups showed improvements in the management of body weight, body mass index, and waist and hip circumference, in addition to improvement in body composition – despite no physical activity components in the programs, the authors note.
“This is probably because both groups followed the same base type 2 diabetes-preventive diet, with the one exception of sardine supplementation, and, although they did not modify their physical activity, both groups reduced their daily caloric intake through food,” the authors note.
The possibility of reducing diabetes risk through dietary changes as opposed to weight loss is especially important in the older population, the authors note, as some studies suggest a link between weight loss in the elderly and an increased risk of mortality.
In a second phase of the study, the researchers say they are evaluating the effect of sardines on the intestinal microbiota, “since it affects the regulation of many biological processes, and we need to understand if they have played a part in this protective effect against type 2 diabetes,” Dr. Díaz-Rizzolo concluded.
The study was funded by RecerCaixa 2013. The authors report that “no industry sponsorship was received for this work that could have influenced its outcome.”
A version of this article first appeared on Medscape.com.
Any bone break increases risk for subsequent fracture in older women
No matter where an initial fracture occurs in a postmenopausal woman, there is a subsequent increased risk of another fracture, with the risk surprisingly highest in the youngest postmenopausal group and among certain minorities, new data indicate.
“To our knowledge, no previous prospective study has reported detailed patterns of subsequent fracture locations after initial fracture according to age strata among women in the U.S.,” the authors noted in their article, published online May 5, 2021, in EClinicalMedicine.
The results show that a first fracture of the lower arm or wrist; upper arm; or shoulder, upper leg, knee, lower leg, or ankle – as well as those of the hip or pelvis – were associated with an approximately three- to sixfold increased risk for subsequent fractures. The findings have important implications for clinicians, said lead author Carolyn J. Crandall, MD, professor of medicine at the University of California, Los Angeles.
“By not paying attention to which types of fractures increase the risk of future fractures, we are missing the opportunity to identify people at increased risk of future fracture and counsel them regarding risk reduction,” she said in a press statement.
Commenting on the research, Michael R. McClung, MD, stressed this message to clinicians needs to be underscored.
“This paper is one of a series of papers highlighting the fact that having a previous fracture is a risk factor for subsequent fractures,” he said in an interview.
“This has been known for a very long time, but it is a point still not appreciated by patients and primary care doctors, so having another study pointing this out is important,” emphasized Dr. McClung, of the Oregon Osteoporosis Center in Portland.
30% of women’s health initiative participants had a fracture
For the study, Dr. Crandall and colleagues evaluated data on 157,282 women between the ages of 50 and 79 who were enrolled in the Women’s Health Initiative between 1993 and 2018.
The women were a mean age of 63.1 years and 47,126 (30%) experienced an incident fracture during the study period.
With a mean follow-up of 15.4 years, each type of fracture was associated with an increased risk of a subsequent fracture after adjusting for age, race/ethnicity, body mass index, hormone therapy use, and other factors.
A wide range of initial risk fractures – including an initial lower arm or wrist fracture (adjusted hazard ratio, 4.80), upper arm or shoulder fracture (aHR, 5.06), upper leg fracture (aHR, 5.11), knee fracture (aHR, 5.03), lower leg/ankle fracture (aHR, 4.10), and spinal fracture (aHR, 6.69) – increased the risk of sustaining a subsequent hip fracture.
For initial fractures of the lower arm or wrist, there was an increased risk of a subsequent fracture of the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (aHRs ranged from 2.63 to 5.68).
“The finding that knee fracture has the same prognostic value for subsequent fracture as hip or wrist fracture is a novel key finding, as knee fracture is generally not considered ‘osteoporotic’,” the authors noted.
The risk of fracture after sustaining an initial hip or pelvis fracture was exceptionally high – with as much as a 27-fold higher risk of a subsequent upper leg (nonhip) fracture (aHR, 27.18).
“Thirty-four percent of women who experienced initial hip or pelvis fracture experienced a subsequent nonhip fracture,” the authors noted.
However, the risks associated with an initial hip fracture are already well established, and the study’s more notable findings are the risks of other bone breaks, Dr. Crandall told this news organization.
“The (increased risk with hip fracture) is a rather substantial result,” she said. “However, the more major point of this study is that no matter where the initial fracture happened, the risk of the future fracture was elevated.”
Don’t disregard risks in younger women, racial/ethnic groups
The findings regarding age are also important. The highest risk was observed in the youngest postmenopausal age group of 50-59 years (aHR, 6.45), which decreased slightly in the 60- to 69-year age group (aHR, 6.04) and further decreased in the 70- to 79-year age group (aHR, 4.99).
“This was a surprise, and it highlights that clinicians should not disregard initial fractures among young postmenopausal women,” Dr. Crandall told this news organization.
Even greater increased risks for a subsequent fracture following an initial lower extremity fracture were observed in non-Hispanic Black women, Hispanic or Latina women, and women of Asian Pacific Islander ethnicity, ranging from ninefold to 14-fold, versus a sevenfold risk among non-Hispanic White women.
“This has public health implications because it means that we may have been missing the opportunity to prevent fractures among younger postmenopausal women and underrepresented racial/ethnic groups,” Dr. Crandall noted.
Is risk greatest 1-2 years after the initial fracture?
The findings suggest that current treatment guidelines may need to be revisited in light of inconsistencies regarding when, and for which fracture types, to initiate treatment.
“It will be important to determine whether existing risk calculators can be adapted (or new calculators developed) to help refine decision-making to determine which of the women with fractures other than hip or vertebral fractures should be treated,” the authors wrote.
Dr. McClung said a randomized, controlled trial of osteoporosis treatment in people who present with all types of fractures would help determine whether having a knee or a wrist fracture does indeed warrant such therapy.
He further commented that future studies should evaluate the shorter- versus longer-term risks.
“The most recent research suggests that the risk of having a second fracture is much higher in the first year or 2 after the first or incident fracture,” he observed. “So, the next stage in research with this dataset would be to ask not what happens over a 10-year time frame but what happens over the first year or 2 after the fracture.”
The study was funded by the National Heart, Lung, and Blood Institute. Dr. Crandall reported no relevant financial relationships. Dr. McClung reported being a consultant and on the speakers bureau for Amgen and being a speaker for Alexion.
A version of this article first appeared on Medscape.com.
No matter where an initial fracture occurs in a postmenopausal woman, there is a subsequent increased risk of another fracture, with the risk surprisingly highest in the youngest postmenopausal group and among certain minorities, new data indicate.
“To our knowledge, no previous prospective study has reported detailed patterns of subsequent fracture locations after initial fracture according to age strata among women in the U.S.,” the authors noted in their article, published online May 5, 2021, in EClinicalMedicine.
The results show that a first fracture of the lower arm or wrist; upper arm; or shoulder, upper leg, knee, lower leg, or ankle – as well as those of the hip or pelvis – were associated with an approximately three- to sixfold increased risk for subsequent fractures. The findings have important implications for clinicians, said lead author Carolyn J. Crandall, MD, professor of medicine at the University of California, Los Angeles.
“By not paying attention to which types of fractures increase the risk of future fractures, we are missing the opportunity to identify people at increased risk of future fracture and counsel them regarding risk reduction,” she said in a press statement.
Commenting on the research, Michael R. McClung, MD, stressed this message to clinicians needs to be underscored.
“This paper is one of a series of papers highlighting the fact that having a previous fracture is a risk factor for subsequent fractures,” he said in an interview.
“This has been known for a very long time, but it is a point still not appreciated by patients and primary care doctors, so having another study pointing this out is important,” emphasized Dr. McClung, of the Oregon Osteoporosis Center in Portland.
30% of women’s health initiative participants had a fracture
For the study, Dr. Crandall and colleagues evaluated data on 157,282 women between the ages of 50 and 79 who were enrolled in the Women’s Health Initiative between 1993 and 2018.
The women were a mean age of 63.1 years and 47,126 (30%) experienced an incident fracture during the study period.
With a mean follow-up of 15.4 years, each type of fracture was associated with an increased risk of a subsequent fracture after adjusting for age, race/ethnicity, body mass index, hormone therapy use, and other factors.
A wide range of initial risk fractures – including an initial lower arm or wrist fracture (adjusted hazard ratio, 4.80), upper arm or shoulder fracture (aHR, 5.06), upper leg fracture (aHR, 5.11), knee fracture (aHR, 5.03), lower leg/ankle fracture (aHR, 4.10), and spinal fracture (aHR, 6.69) – increased the risk of sustaining a subsequent hip fracture.
For initial fractures of the lower arm or wrist, there was an increased risk of a subsequent fracture of the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (aHRs ranged from 2.63 to 5.68).
“The finding that knee fracture has the same prognostic value for subsequent fracture as hip or wrist fracture is a novel key finding, as knee fracture is generally not considered ‘osteoporotic’,” the authors noted.
The risk of fracture after sustaining an initial hip or pelvis fracture was exceptionally high – with as much as a 27-fold higher risk of a subsequent upper leg (nonhip) fracture (aHR, 27.18).
“Thirty-four percent of women who experienced initial hip or pelvis fracture experienced a subsequent nonhip fracture,” the authors noted.
However, the risks associated with an initial hip fracture are already well established, and the study’s more notable findings are the risks of other bone breaks, Dr. Crandall told this news organization.
“The (increased risk with hip fracture) is a rather substantial result,” she said. “However, the more major point of this study is that no matter where the initial fracture happened, the risk of the future fracture was elevated.”
Don’t disregard risks in younger women, racial/ethnic groups
The findings regarding age are also important. The highest risk was observed in the youngest postmenopausal age group of 50-59 years (aHR, 6.45), which decreased slightly in the 60- to 69-year age group (aHR, 6.04) and further decreased in the 70- to 79-year age group (aHR, 4.99).
“This was a surprise, and it highlights that clinicians should not disregard initial fractures among young postmenopausal women,” Dr. Crandall told this news organization.
Even greater increased risks for a subsequent fracture following an initial lower extremity fracture were observed in non-Hispanic Black women, Hispanic or Latina women, and women of Asian Pacific Islander ethnicity, ranging from ninefold to 14-fold, versus a sevenfold risk among non-Hispanic White women.
“This has public health implications because it means that we may have been missing the opportunity to prevent fractures among younger postmenopausal women and underrepresented racial/ethnic groups,” Dr. Crandall noted.
Is risk greatest 1-2 years after the initial fracture?
The findings suggest that current treatment guidelines may need to be revisited in light of inconsistencies regarding when, and for which fracture types, to initiate treatment.
“It will be important to determine whether existing risk calculators can be adapted (or new calculators developed) to help refine decision-making to determine which of the women with fractures other than hip or vertebral fractures should be treated,” the authors wrote.
Dr. McClung said a randomized, controlled trial of osteoporosis treatment in people who present with all types of fractures would help determine whether having a knee or a wrist fracture does indeed warrant such therapy.
He further commented that future studies should evaluate the shorter- versus longer-term risks.
“The most recent research suggests that the risk of having a second fracture is much higher in the first year or 2 after the first or incident fracture,” he observed. “So, the next stage in research with this dataset would be to ask not what happens over a 10-year time frame but what happens over the first year or 2 after the fracture.”
The study was funded by the National Heart, Lung, and Blood Institute. Dr. Crandall reported no relevant financial relationships. Dr. McClung reported being a consultant and on the speakers bureau for Amgen and being a speaker for Alexion.
A version of this article first appeared on Medscape.com.
No matter where an initial fracture occurs in a postmenopausal woman, there is a subsequent increased risk of another fracture, with the risk surprisingly highest in the youngest postmenopausal group and among certain minorities, new data indicate.
“To our knowledge, no previous prospective study has reported detailed patterns of subsequent fracture locations after initial fracture according to age strata among women in the U.S.,” the authors noted in their article, published online May 5, 2021, in EClinicalMedicine.
The results show that a first fracture of the lower arm or wrist; upper arm; or shoulder, upper leg, knee, lower leg, or ankle – as well as those of the hip or pelvis – were associated with an approximately three- to sixfold increased risk for subsequent fractures. The findings have important implications for clinicians, said lead author Carolyn J. Crandall, MD, professor of medicine at the University of California, Los Angeles.
“By not paying attention to which types of fractures increase the risk of future fractures, we are missing the opportunity to identify people at increased risk of future fracture and counsel them regarding risk reduction,” she said in a press statement.
Commenting on the research, Michael R. McClung, MD, stressed this message to clinicians needs to be underscored.
“This paper is one of a series of papers highlighting the fact that having a previous fracture is a risk factor for subsequent fractures,” he said in an interview.
“This has been known for a very long time, but it is a point still not appreciated by patients and primary care doctors, so having another study pointing this out is important,” emphasized Dr. McClung, of the Oregon Osteoporosis Center in Portland.
30% of women’s health initiative participants had a fracture
For the study, Dr. Crandall and colleagues evaluated data on 157,282 women between the ages of 50 and 79 who were enrolled in the Women’s Health Initiative between 1993 and 2018.
The women were a mean age of 63.1 years and 47,126 (30%) experienced an incident fracture during the study period.
With a mean follow-up of 15.4 years, each type of fracture was associated with an increased risk of a subsequent fracture after adjusting for age, race/ethnicity, body mass index, hormone therapy use, and other factors.
A wide range of initial risk fractures – including an initial lower arm or wrist fracture (adjusted hazard ratio, 4.80), upper arm or shoulder fracture (aHR, 5.06), upper leg fracture (aHR, 5.11), knee fracture (aHR, 5.03), lower leg/ankle fracture (aHR, 4.10), and spinal fracture (aHR, 6.69) – increased the risk of sustaining a subsequent hip fracture.
For initial fractures of the lower arm or wrist, there was an increased risk of a subsequent fracture of the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (aHRs ranged from 2.63 to 5.68).
“The finding that knee fracture has the same prognostic value for subsequent fracture as hip or wrist fracture is a novel key finding, as knee fracture is generally not considered ‘osteoporotic’,” the authors noted.
The risk of fracture after sustaining an initial hip or pelvis fracture was exceptionally high – with as much as a 27-fold higher risk of a subsequent upper leg (nonhip) fracture (aHR, 27.18).
“Thirty-four percent of women who experienced initial hip or pelvis fracture experienced a subsequent nonhip fracture,” the authors noted.
However, the risks associated with an initial hip fracture are already well established, and the study’s more notable findings are the risks of other bone breaks, Dr. Crandall told this news organization.
“The (increased risk with hip fracture) is a rather substantial result,” she said. “However, the more major point of this study is that no matter where the initial fracture happened, the risk of the future fracture was elevated.”
Don’t disregard risks in younger women, racial/ethnic groups
The findings regarding age are also important. The highest risk was observed in the youngest postmenopausal age group of 50-59 years (aHR, 6.45), which decreased slightly in the 60- to 69-year age group (aHR, 6.04) and further decreased in the 70- to 79-year age group (aHR, 4.99).
“This was a surprise, and it highlights that clinicians should not disregard initial fractures among young postmenopausal women,” Dr. Crandall told this news organization.
Even greater increased risks for a subsequent fracture following an initial lower extremity fracture were observed in non-Hispanic Black women, Hispanic or Latina women, and women of Asian Pacific Islander ethnicity, ranging from ninefold to 14-fold, versus a sevenfold risk among non-Hispanic White women.
“This has public health implications because it means that we may have been missing the opportunity to prevent fractures among younger postmenopausal women and underrepresented racial/ethnic groups,” Dr. Crandall noted.
Is risk greatest 1-2 years after the initial fracture?
The findings suggest that current treatment guidelines may need to be revisited in light of inconsistencies regarding when, and for which fracture types, to initiate treatment.
“It will be important to determine whether existing risk calculators can be adapted (or new calculators developed) to help refine decision-making to determine which of the women with fractures other than hip or vertebral fractures should be treated,” the authors wrote.
Dr. McClung said a randomized, controlled trial of osteoporosis treatment in people who present with all types of fractures would help determine whether having a knee or a wrist fracture does indeed warrant such therapy.
He further commented that future studies should evaluate the shorter- versus longer-term risks.
“The most recent research suggests that the risk of having a second fracture is much higher in the first year or 2 after the first or incident fracture,” he observed. “So, the next stage in research with this dataset would be to ask not what happens over a 10-year time frame but what happens over the first year or 2 after the fracture.”
The study was funded by the National Heart, Lung, and Blood Institute. Dr. Crandall reported no relevant financial relationships. Dr. McClung reported being a consultant and on the speakers bureau for Amgen and being a speaker for Alexion.
A version of this article first appeared on Medscape.com.