Andrew D. Bowser

Dabrafenib plus trametinib treatment was associated with a 5-year overall survival rate of 34% in patients with melanoma harboring a BRAF V600E or V600K mutation, according to a combined analysis of two trials.

The 5-year progression-free survival rate was 19% in the long-term, pooled analysis of the COMBI-d and COMBI-v trials, which included at total of 563 patients with previously untreated, unresectable or metastatic melanoma who received combined treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib.

Previously reported 5-year progression-free survival rates for patients treated with anti–programmed death-1 checkpoint inhibitors, either nivolumab or pembrolizumab, “appear to be similar” to these results for dabrafenib plus trametinib, investigators said in a report on the analysis appearing in the New England Journal of Medicine.

To date, however, 5-year survival data have not been reported for other BRAF-targeted therapies, according to the investigators, who were led by Caroline Robert, MD, PhD, of Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif, France.

“These data will be critical to assess the potential of therapy to exert long-term disease control through analysis of survival plateaus and to understand factors predictive of long-term survival,” Dr. Robert and coauthors wrote in their report.

A total of 211 patients in the COMBI-d trial were randomly allocated to receive the combination of dabrafenib plus trametinib, while in COMBI-v, 352 received this combination therapy, according to investigators.

Notably, the survival curves for dabrafenib plus trametinib appear to plateau starting at 3 years, investigators reported. In a previously published report on pooled COMBI-d and COMBI-v data, the 3-year progression-free survival rate was 23%, and the 3-year overall survival rate was 44%.

In this more recent analysis, progression-free survival rates were 21% at 4 years and 19% at 5 years, while overall survival rates were 37% at 4 years and 34% at 5 years.

“This finding suggests stabilization of rates of progression-free survival and overall survival over time in this population,” Dr. Robert and colleagues wrote.

Survival rates were higher in patients with normal lactate dehydrogenase (LDH) levels at baseline, and they were especially high in those with normal LDH and three or fewer disease sites at baseline, according to the report. Specifically, the reported 5-year rates of progression-free and overall survival were 31% and 55%, respectively.

Other factors associated with prolonged progression-free survival included female sex, older age, better performance status, and BRAF V600E genotype, according to results of a multivariate analysis that investigators said confirmed findings from the previously reported 3-year data.

The study was supported by GlaxoSmithKline and Novartis. Dr. Robert provided disclosures related to BMS, Pierre Fabre, Novartis, Amgen, Merck, Roche, MSD, and Sanofi.

SOURCE: Robert C et al. N Engl J Med. 2019 Aug 15. doi: 10.1056/NEJMoa1904059

Dabrafenib plus trametinib treatment was associated with a 5-year overall survival rate of 34% in patients with melanoma harboring a BRAF V600E or V600K mutation, according to a combined analysis of two trials.

The 5-year progression-free survival rate was 19% in the long-term, pooled analysis of the COMBI-d and COMBI-v trials, which included at total of 563 patients with previously untreated, unresectable or metastatic melanoma who received combined treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib.

Previously reported 5-year progression-free survival rates for patients treated with anti–programmed death-1 checkpoint inhibitors, either nivolumab or pembrolizumab, “appear to be similar” to these results for dabrafenib plus trametinib, investigators said in a report on the analysis appearing in the New England Journal of Medicine.

To date, however, 5-year survival data have not been reported for other BRAF-targeted therapies, according to the investigators, who were led by Caroline Robert, MD, PhD, of Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif, France.

“These data will be critical to assess the potential of therapy to exert long-term disease control through analysis of survival plateaus and to understand factors predictive of long-term survival,” Dr. Robert and coauthors wrote in their report.

A total of 211 patients in the COMBI-d trial were randomly allocated to receive the combination of dabrafenib plus trametinib, while in COMBI-v, 352 received this combination therapy, according to investigators.

Notably, the survival curves for dabrafenib plus trametinib appear to plateau starting at 3 years, investigators reported. In a previously published report on pooled COMBI-d and COMBI-v data, the 3-year progression-free survival rate was 23%, and the 3-year overall survival rate was 44%.

In this more recent analysis, progression-free survival rates were 21% at 4 years and 19% at 5 years, while overall survival rates were 37% at 4 years and 34% at 5 years.

“This finding suggests stabilization of rates of progression-free survival and overall survival over time in this population,” Dr. Robert and colleagues wrote.

Survival rates were higher in patients with normal lactate dehydrogenase (LDH) levels at baseline, and they were especially high in those with normal LDH and three or fewer disease sites at baseline, according to the report. Specifically, the reported 5-year rates of progression-free and overall survival were 31% and 55%, respectively.

Other factors associated with prolonged progression-free survival included female sex, older age, better performance status, and BRAF V600E genotype, according to results of a multivariate analysis that investigators said confirmed findings from the previously reported 3-year data.

The study was supported by GlaxoSmithKline and Novartis. Dr. Robert provided disclosures related to BMS, Pierre Fabre, Novartis, Amgen, Merck, Roche, MSD, and Sanofi.

SOURCE: Robert C et al. N Engl J Med. 2019 Aug 15. doi: 10.1056/NEJMoa1904059

Dabrafenib plus trametinib treatment was associated with a 5-year overall survival rate of 34% in patients with melanoma harboring a BRAF V600E or V600K mutation, according to a combined analysis of two trials.

The 5-year progression-free survival rate was 19% in the long-term, pooled analysis of the COMBI-d and COMBI-v trials, which included at total of 563 patients with previously untreated, unresectable or metastatic melanoma who received combined treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib.

Previously reported 5-year progression-free survival rates for patients treated with anti–programmed death-1 checkpoint inhibitors, either nivolumab or pembrolizumab, “appear to be similar” to these results for dabrafenib plus trametinib, investigators said in a report on the analysis appearing in the New England Journal of Medicine.

To date, however, 5-year survival data have not been reported for other BRAF-targeted therapies, according to the investigators, who were led by Caroline Robert, MD, PhD, of Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif, France.

“These data will be critical to assess the potential of therapy to exert long-term disease control through analysis of survival plateaus and to understand factors predictive of long-term survival,” Dr. Robert and coauthors wrote in their report.

A total of 211 patients in the COMBI-d trial were randomly allocated to receive the combination of dabrafenib plus trametinib, while in COMBI-v, 352 received this combination therapy, according to investigators.

Notably, the survival curves for dabrafenib plus trametinib appear to plateau starting at 3 years, investigators reported. In a previously published report on pooled COMBI-d and COMBI-v data, the 3-year progression-free survival rate was 23%, and the 3-year overall survival rate was 44%.

In this more recent analysis, progression-free survival rates were 21% at 4 years and 19% at 5 years, while overall survival rates were 37% at 4 years and 34% at 5 years.

“This finding suggests stabilization of rates of progression-free survival and overall survival over time in this population,” Dr. Robert and colleagues wrote.

Survival rates were higher in patients with normal lactate dehydrogenase (LDH) levels at baseline, and they were especially high in those with normal LDH and three or fewer disease sites at baseline, according to the report. Specifically, the reported 5-year rates of progression-free and overall survival were 31% and 55%, respectively.

Other factors associated with prolonged progression-free survival included female sex, older age, better performance status, and BRAF V600E genotype, according to results of a multivariate analysis that investigators said confirmed findings from the previously reported 3-year data.

The study was supported by GlaxoSmithKline and Novartis. Dr. Robert provided disclosures related to BMS, Pierre Fabre, Novartis, Amgen, Merck, Roche, MSD, and Sanofi.

SOURCE: Robert C et al. N Engl J Med. 2019 Aug 15. doi: 10.1056/NEJMoa1904059

The first-in-class antiretroviral therapy islatravir (Merck) was well tolerated and had promising efficacy in a phase 2B study including treatment-naive adults with HIV-1 infection, supporting plans to initiate a phase 3 trial, an investigator said at the International AIDS Society Conference on HIV Science.

MattZ90/Thinkstock.com

The proportion of patients achieving viral suppression at week 48 with combinations including the nucleoside transcriptase translocation inhibitor (NRTTI) was comparable to what was achieved with a standard triple regimen, said investigator Jean-Michel Molina, MD, professor of infectious diseases at the University of Paris Diderot, and head of the infectious diseases department at the Saint-Louis Hospital in Paris

The treatment was effective not only as part of a three-drug combination of islatravir, doravirine, and lamivudine over 24 weeks, but also over an additional 24 weeks in patients who achieved viral suppression and were switched to dual therapy with islatravir and doravirine, according to Dr. Molina.

“These are promising data that will encourage the company to move to a phase 3 trial to see how these results can be confirmed in a larger study set, and also to assess the potency of the dual combination for maintenance therapy in the future, providing also novel options for people with a drug that has a high genetic barrier to resistance and efficacy that seems to be quite interesting,” Dr. Molina said in an IAS press conference in Mexico City.

This drug has very potent activity not only against wild-type HIV-1 viruses, but also multiresistant viruses, according to Dr. Molina.

“It has a high inhibitory quotient at a very low dose, so you give people a tiny amount of drug – in the range of 1 milligram per day, instead of a few hundred milligrams with other, regular drugs,” he said.

Another attribute of islatravir is its long half-life of approximately 120 hours, allowing not only for once-daily dosing, but potentially for evaluation as once-weekly or once-monthly dosing in the future, he said, adding that a subdermal islatravir-eluting implant under investigation for preexposure prophylaxis has potential as a once-yearly option.

The international, multicenter, 121-patient clinical trial that Dr. Molina described included adults with HIV-1 infection naive to antiretroviral therapy randomized to islatravir (in one of three doses) plus doravirine and lamivudine, or to the combination of doravirine, lamivudine, and tenofovir (Delstrigo, Merck).

After at least 24 weeks of treatment, subjects in the islatravir treatment groups were transitioned to the two-drug combination of islatravir and doravirine if they had HIV-1 RNA levels less than 50 copies/mL and did not meet any protocol-defined criteria for virologic failure.

Those participants in the islatravir arms who received 48 weeks of treatment had “very good response” and safety that was comparable to the control arm, according to Dr. Molina.

At 48 weeks, the proportion of patients with HIV-1 RNA less than 50 copies/mL were 89.7%, 90%, and 77.4% for regimens containing islatravir 0.25 mg, 0.75 mg, and 2.25 mg, respectively, and 83.9% for those receiving the standard triple therapy, according to reported data.

All patients with protocol-defined virologic failure (greater than or equal to 50 copies/mL) in the study actually had very low viral load, below 80 copies/mL, Dr. Molina said.

The study was supported by Merck. Dr. Molina has been on the Merck advisory board and speaker’s bureau.

SOURCE: Molina J-M et al. IAS 2019, Abstract WEAB0402LB.

The first-in-class antiretroviral therapy islatravir (Merck) was well tolerated and had promising efficacy in a phase 2B study including treatment-naive adults with HIV-1 infection, supporting plans to initiate a phase 3 trial, an investigator said at the International AIDS Society Conference on HIV Science.

MattZ90/Thinkstock.com

The proportion of patients achieving viral suppression at week 48 with combinations including the nucleoside transcriptase translocation inhibitor (NRTTI) was comparable to what was achieved with a standard triple regimen, said investigator Jean-Michel Molina, MD, professor of infectious diseases at the University of Paris Diderot, and head of the infectious diseases department at the Saint-Louis Hospital in Paris

The treatment was effective not only as part of a three-drug combination of islatravir, doravirine, and lamivudine over 24 weeks, but also over an additional 24 weeks in patients who achieved viral suppression and were switched to dual therapy with islatravir and doravirine, according to Dr. Molina.

“These are promising data that will encourage the company to move to a phase 3 trial to see how these results can be confirmed in a larger study set, and also to assess the potency of the dual combination for maintenance therapy in the future, providing also novel options for people with a drug that has a high genetic barrier to resistance and efficacy that seems to be quite interesting,” Dr. Molina said in an IAS press conference in Mexico City.

This drug has very potent activity not only against wild-type HIV-1 viruses, but also multiresistant viruses, according to Dr. Molina.

“It has a high inhibitory quotient at a very low dose, so you give people a tiny amount of drug – in the range of 1 milligram per day, instead of a few hundred milligrams with other, regular drugs,” he said.

Another attribute of islatravir is its long half-life of approximately 120 hours, allowing not only for once-daily dosing, but potentially for evaluation as once-weekly or once-monthly dosing in the future, he said, adding that a subdermal islatravir-eluting implant under investigation for preexposure prophylaxis has potential as a once-yearly option.

The international, multicenter, 121-patient clinical trial that Dr. Molina described included adults with HIV-1 infection naive to antiretroviral therapy randomized to islatravir (in one of three doses) plus doravirine and lamivudine, or to the combination of doravirine, lamivudine, and tenofovir (Delstrigo, Merck).

After at least 24 weeks of treatment, subjects in the islatravir treatment groups were transitioned to the two-drug combination of islatravir and doravirine if they had HIV-1 RNA levels less than 50 copies/mL and did not meet any protocol-defined criteria for virologic failure.

Those participants in the islatravir arms who received 48 weeks of treatment had “very good response” and safety that was comparable to the control arm, according to Dr. Molina.

At 48 weeks, the proportion of patients with HIV-1 RNA less than 50 copies/mL were 89.7%, 90%, and 77.4% for regimens containing islatravir 0.25 mg, 0.75 mg, and 2.25 mg, respectively, and 83.9% for those receiving the standard triple therapy, according to reported data.

All patients with protocol-defined virologic failure (greater than or equal to 50 copies/mL) in the study actually had very low viral load, below 80 copies/mL, Dr. Molina said.

The study was supported by Merck. Dr. Molina has been on the Merck advisory board and speaker’s bureau.

SOURCE: Molina J-M et al. IAS 2019, Abstract WEAB0402LB.

The first-in-class antiretroviral therapy islatravir (Merck) was well tolerated and had promising efficacy in a phase 2B study including treatment-naive adults with HIV-1 infection, supporting plans to initiate a phase 3 trial, an investigator said at the International AIDS Society Conference on HIV Science.

MattZ90/Thinkstock.com

The proportion of patients achieving viral suppression at week 48 with combinations including the nucleoside transcriptase translocation inhibitor (NRTTI) was comparable to what was achieved with a standard triple regimen, said investigator Jean-Michel Molina, MD, professor of infectious diseases at the University of Paris Diderot, and head of the infectious diseases department at the Saint-Louis Hospital in Paris

The treatment was effective not only as part of a three-drug combination of islatravir, doravirine, and lamivudine over 24 weeks, but also over an additional 24 weeks in patients who achieved viral suppression and were switched to dual therapy with islatravir and doravirine, according to Dr. Molina.

“These are promising data that will encourage the company to move to a phase 3 trial to see how these results can be confirmed in a larger study set, and also to assess the potency of the dual combination for maintenance therapy in the future, providing also novel options for people with a drug that has a high genetic barrier to resistance and efficacy that seems to be quite interesting,” Dr. Molina said in an IAS press conference in Mexico City.

This drug has very potent activity not only against wild-type HIV-1 viruses, but also multiresistant viruses, according to Dr. Molina.

“It has a high inhibitory quotient at a very low dose, so you give people a tiny amount of drug – in the range of 1 milligram per day, instead of a few hundred milligrams with other, regular drugs,” he said.

Another attribute of islatravir is its long half-life of approximately 120 hours, allowing not only for once-daily dosing, but potentially for evaluation as once-weekly or once-monthly dosing in the future, he said, adding that a subdermal islatravir-eluting implant under investigation for preexposure prophylaxis has potential as a once-yearly option.

The international, multicenter, 121-patient clinical trial that Dr. Molina described included adults with HIV-1 infection naive to antiretroviral therapy randomized to islatravir (in one of three doses) plus doravirine and lamivudine, or to the combination of doravirine, lamivudine, and tenofovir (Delstrigo, Merck).

After at least 24 weeks of treatment, subjects in the islatravir treatment groups were transitioned to the two-drug combination of islatravir and doravirine if they had HIV-1 RNA levels less than 50 copies/mL and did not meet any protocol-defined criteria for virologic failure.

Those participants in the islatravir arms who received 48 weeks of treatment had “very good response” and safety that was comparable to the control arm, according to Dr. Molina.

At 48 weeks, the proportion of patients with HIV-1 RNA less than 50 copies/mL were 89.7%, 90%, and 77.4% for regimens containing islatravir 0.25 mg, 0.75 mg, and 2.25 mg, respectively, and 83.9% for those receiving the standard triple therapy, according to reported data.

All patients with protocol-defined virologic failure (greater than or equal to 50 copies/mL) in the study actually had very low viral load, below 80 copies/mL, Dr. Molina said.

The study was supported by Merck. Dr. Molina has been on the Merck advisory board and speaker’s bureau.

SOURCE: Molina J-M et al. IAS 2019, Abstract WEAB0402LB.

An implant that elutes an investigational antiretroviral agent provided drug release that should be sufficient for HIV prophylaxis for 12 months or more, according to results of a phase 1 clinical trial just presented here at the International AIDS Society Conference on HIV Science.

grandeduc/Thinkstock

The islatravir-eluting arm implant was safe and generally well tolerated, with drug concentrations that remained above the target level needed for protection throughout the randomized, placebo-controlled study, said investigator Randolph P. Matthews, MD, PhD, senior principal scientist at Merck, Kenilworth, N.J.

“Based on this study, the islatravir-eluting implant appears to be a potentially important option for preexposure prophylaxis (PrEP) as an agent that could be effective with yearly dosing,” Dr. Matthews said in an IAS press conference.

This drug-eluting implant, inserted subdermally in the skin of the upper arm, could represent a “meaningful option” for many individuals at high risk of HIV infection, particularly those who have adherence challenges, said Dr. Matthews.

“Many at-risk individuals face adherence challenges with the existing daily oral PrEP therapy,” he added. “A high degree of adherence is required for it to be effective, and daily adherence is challenging for many, particularly for women.”

Islatravir, formerly known as MK-8591, is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) being evaluated in clinical trials not only for PrEP, but also for treatment of HIV-1 infection in combination with other antiretrovirals.

In preclinical trials, islatravir demonstrated high potency, a high barrier to resistance, and a long half-life, according to Dr. Matthews.

The phase 1, single-site, double-blind study included a total of 16 healthy adult volunteers who received implants of islatravir at one of two doses (54 mg and 62 mg) or placebo for 12 weeks.

Both active doses of islatravir led to concentrations above the target level at 12 weeks, and based on data modeling, the higher-dose implant would still be above the target level for at least a year, Dr. Matthews said in the press conference.

The projected duration above the target ranged from 12 to 16 months for the 62-mg dose of islatravir, and from 8 to 10 months for the 54-mg dose, according to the reported data.

All drug-related adverse events were mild or moderate in severity, and none of the volunteers discontinued the study because of an adverse event, Dr. Matthews said.

Taken together, these data support the continued progression of the implant clinical development program, said Dr. Matthews, who is an employee of Merck, which sponsored the study.

SOURCE: Matthews RP et al. IAS 2019, Abstract TUAC0401LB.

An implant that elutes an investigational antiretroviral agent provided drug release that should be sufficient for HIV prophylaxis for 12 months or more, according to results of a phase 1 clinical trial just presented here at the International AIDS Society Conference on HIV Science.

grandeduc/Thinkstock

The islatravir-eluting arm implant was safe and generally well tolerated, with drug concentrations that remained above the target level needed for protection throughout the randomized, placebo-controlled study, said investigator Randolph P. Matthews, MD, PhD, senior principal scientist at Merck, Kenilworth, N.J.

“Based on this study, the islatravir-eluting implant appears to be a potentially important option for preexposure prophylaxis (PrEP) as an agent that could be effective with yearly dosing,” Dr. Matthews said in an IAS press conference.

This drug-eluting implant, inserted subdermally in the skin of the upper arm, could represent a “meaningful option” for many individuals at high risk of HIV infection, particularly those who have adherence challenges, said Dr. Matthews.

“Many at-risk individuals face adherence challenges with the existing daily oral PrEP therapy,” he added. “A high degree of adherence is required for it to be effective, and daily adherence is challenging for many, particularly for women.”

Islatravir, formerly known as MK-8591, is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) being evaluated in clinical trials not only for PrEP, but also for treatment of HIV-1 infection in combination with other antiretrovirals.

In preclinical trials, islatravir demonstrated high potency, a high barrier to resistance, and a long half-life, according to Dr. Matthews.

The phase 1, single-site, double-blind study included a total of 16 healthy adult volunteers who received implants of islatravir at one of two doses (54 mg and 62 mg) or placebo for 12 weeks.

Both active doses of islatravir led to concentrations above the target level at 12 weeks, and based on data modeling, the higher-dose implant would still be above the target level for at least a year, Dr. Matthews said in the press conference.

The projected duration above the target ranged from 12 to 16 months for the 62-mg dose of islatravir, and from 8 to 10 months for the 54-mg dose, according to the reported data.

All drug-related adverse events were mild or moderate in severity, and none of the volunteers discontinued the study because of an adverse event, Dr. Matthews said.

Taken together, these data support the continued progression of the implant clinical development program, said Dr. Matthews, who is an employee of Merck, which sponsored the study.

SOURCE: Matthews RP et al. IAS 2019, Abstract TUAC0401LB.

An implant that elutes an investigational antiretroviral agent provided drug release that should be sufficient for HIV prophylaxis for 12 months or more, according to results of a phase 1 clinical trial just presented here at the International AIDS Society Conference on HIV Science.

grandeduc/Thinkstock

The islatravir-eluting arm implant was safe and generally well tolerated, with drug concentrations that remained above the target level needed for protection throughout the randomized, placebo-controlled study, said investigator Randolph P. Matthews, MD, PhD, senior principal scientist at Merck, Kenilworth, N.J.

“Based on this study, the islatravir-eluting implant appears to be a potentially important option for preexposure prophylaxis (PrEP) as an agent that could be effective with yearly dosing,” Dr. Matthews said in an IAS press conference.

This drug-eluting implant, inserted subdermally in the skin of the upper arm, could represent a “meaningful option” for many individuals at high risk of HIV infection, particularly those who have adherence challenges, said Dr. Matthews.

“Many at-risk individuals face adherence challenges with the existing daily oral PrEP therapy,” he added. “A high degree of adherence is required for it to be effective, and daily adherence is challenging for many, particularly for women.”

Islatravir, formerly known as MK-8591, is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) being evaluated in clinical trials not only for PrEP, but also for treatment of HIV-1 infection in combination with other antiretrovirals.

In preclinical trials, islatravir demonstrated high potency, a high barrier to resistance, and a long half-life, according to Dr. Matthews.

The phase 1, single-site, double-blind study included a total of 16 healthy adult volunteers who received implants of islatravir at one of two doses (54 mg and 62 mg) or placebo for 12 weeks.

Both active doses of islatravir led to concentrations above the target level at 12 weeks, and based on data modeling, the higher-dose implant would still be above the target level for at least a year, Dr. Matthews said in the press conference.

The projected duration above the target ranged from 12 to 16 months for the 62-mg dose of islatravir, and from 8 to 10 months for the 54-mg dose, according to the reported data.

All drug-related adverse events were mild or moderate in severity, and none of the volunteers discontinued the study because of an adverse event, Dr. Matthews said.

Taken together, these data support the continued progression of the implant clinical development program, said Dr. Matthews, who is an employee of Merck, which sponsored the study.

SOURCE: Matthews RP et al. IAS 2019, Abstract TUAC0401LB.

New studies of a two-drug, integrase inhibitor–based regimen, presented at the International AIDS Society Conference on HIV Science, provide additional data to challenge the three-drug HIV treatment paradigm.

In the results of one study, known as TANGO (NCT03446573), switching to the fixed-dose combination of dolutegravir (DTG) plus lamivudine (3TC) from a tenofovir alafenamide (TAF)–based three- or four-drug regimen maintained virologic suppression at 48 weeks in HIV-1 infected adults, an investigator said, and was noninferior to continuing TAF-based therapy.

In another presentation, updating results of the GEMINI-1 (NCT02831673) and GEMINI-2 studies (NCT02831764), a researcher said the DTG+3TC combination remained noninferior to DTG plus tenofovir/emtricitabine (TDF/FTC) at week 96 in antiretroviral (ART) treatment-naive adults with HIV-1 infection, with no treatment-emergent resistance and no increase in risk of virologic failure.

In light of these findings and encouraging findings from studies of other two-drug regimens, it may be time to “rethink the position of dual therapy in the international guidelines,” according to IAS Past President Pedro Cahn, MD, PhD, of Fundación Huésped, Buenos Aires, who presented the updated GEMINI study results.

“We don’t mean to say now everything should be dual therapy, and we are going to wipe out all other options, but I think we have another strong option for initiating therapy, and probably also for switch therapy,” Dr. Cahn said in a press conference.

Dr. Cahn presented an updated analysis of GEMINI-1 and GEMINI-2, two identically designed phase 3 randomized clinical trials including a total of 1,400 patients.

The 48-week results from those trials, presented in 2018, showed for the first time that a dual-therapy combination of an integrase inhibitor with 3TC was noninferior to the triple-drug regimen of DTG+TDF/FTC, Dr. Cahn said.

In the updated analysis, including 96 weeks of data, the two-drug regimen remained noninferior to the three-drug regimen, according to the investigator.

A total of 11 patients on DTG+3TC and 7 on DTG+TDF/FTC met virologic withdrawal criteria through week 96, with no treatment-emergent resistance mutations seen in either arm, according to results reported in the study abstract.

The proportion of subjects with plasma HIV-1 RNA below 50 c/mL at week 96 was 86% for the two-drug regimen and 90% for the three-drug regimen (adjusted difference, –3.4; 95% confidence interval, –6.7 to 0.0), the reported data showed.

Drug-related adverse events were numerically more common in the three-drug arm, though rates of adverse event–related withdrawal were low in both arms, according to investigators.

The strategy of switching to DTG+3TC was evaluated in the randomized, phase 3 TANGO trial, which included 741 subjects who were already virally suppressed on a TAF-based three- or four-drug regimen. After 48 weeks of therapy, the two-drug regimen was noninferior to remaining on TAF-based therapy in terms of achieving and maintaining viral suppression, according to investigator Jean van Wyk, MB, ChB, Global Medical Lead for dolutegravir at ViiV Healthcare.

Safety outcomes were similar between the arms, though the absolute number of treatment-related adverse events was higher in the DTG+3TC arm “as expected in a switch study,” Dr. van Wyk said.

The percentage of subjects withdrawing from the study because of adverse events was 4% in the DTG+3TC arm and less than 1% in the TAF-based treatment arm, according to reported data.

And with regard to safety there were similar outcomes between the two arms, with regard to overall adverse events, “but as expected in a switch study, we did see more treatment-related adverse events in the dolutegravir plus lamivudine arm, and that’s because the majority of patients were on two new agents in the form of dolutegravir plus lamivudine, so it’s completely expected,” Dr. van Wyk said.

The study met its primary endpoint for noninferiority at week 48, based on the Food and Drug Administration snapshot algorithm. Results showed that switching to DTG+3TC was noninferior to continuing the TAF-containing regimen at week 48, with virologic failure per snapshot criteria seen in less than 1% of subjects in either arm, according to reported data. The proportion of subjects with plasma HIV-1 RNA less than 50 c/mL was 93.2% and 93.0% for the DTG+3TC and TAF-based treatment arms, respectively.

Longer-term follow-up will be important to confirm the noninferiority of the two-drug approach, Dr. van Wyk and Dr. Cahn said in the press conference. The TANGO study of the switch strategy will continue through 148 weeks, while an additional year of follow-up is ongoing for the GEMINI studies of the initial therapy approach.

TANGO and both GEMINI 1 and GEMINI 2 were sponsored by ViiV Healthcare. Dr. van Wyk is an employee of ViiV Healthcare. Dr. Cahn has received research support grants, and fees as consultant and speaker from ViiV Healthcare.

SOURCE: Cahn P et al. IAS 2019, Abstract WEAB0404LB; van Wyk J et al. IAS 2019, Abstract WEAB0403LB.

New studies of a two-drug, integrase inhibitor–based regimen, presented at the International AIDS Society Conference on HIV Science, provide additional data to challenge the three-drug HIV treatment paradigm.

In the results of one study, known as TANGO (NCT03446573), switching to the fixed-dose combination of dolutegravir (DTG) plus lamivudine (3TC) from a tenofovir alafenamide (TAF)–based three- or four-drug regimen maintained virologic suppression at 48 weeks in HIV-1 infected adults, an investigator said, and was noninferior to continuing TAF-based therapy.

In another presentation, updating results of the GEMINI-1 (NCT02831673) and GEMINI-2 studies (NCT02831764), a researcher said the DTG+3TC combination remained noninferior to DTG plus tenofovir/emtricitabine (TDF/FTC) at week 96 in antiretroviral (ART) treatment-naive adults with HIV-1 infection, with no treatment-emergent resistance and no increase in risk of virologic failure.

In light of these findings and encouraging findings from studies of other two-drug regimens, it may be time to “rethink the position of dual therapy in the international guidelines,” according to IAS Past President Pedro Cahn, MD, PhD, of Fundación Huésped, Buenos Aires, who presented the updated GEMINI study results.

“We don’t mean to say now everything should be dual therapy, and we are going to wipe out all other options, but I think we have another strong option for initiating therapy, and probably also for switch therapy,” Dr. Cahn said in a press conference.

Dr. Cahn presented an updated analysis of GEMINI-1 and GEMINI-2, two identically designed phase 3 randomized clinical trials including a total of 1,400 patients.

The 48-week results from those trials, presented in 2018, showed for the first time that a dual-therapy combination of an integrase inhibitor with 3TC was noninferior to the triple-drug regimen of DTG+TDF/FTC, Dr. Cahn said.

In the updated analysis, including 96 weeks of data, the two-drug regimen remained noninferior to the three-drug regimen, according to the investigator.

A total of 11 patients on DTG+3TC and 7 on DTG+TDF/FTC met virologic withdrawal criteria through week 96, with no treatment-emergent resistance mutations seen in either arm, according to results reported in the study abstract.

The proportion of subjects with plasma HIV-1 RNA below 50 c/mL at week 96 was 86% for the two-drug regimen and 90% for the three-drug regimen (adjusted difference, –3.4; 95% confidence interval, –6.7 to 0.0), the reported data showed.

Drug-related adverse events were numerically more common in the three-drug arm, though rates of adverse event–related withdrawal were low in both arms, according to investigators.

The strategy of switching to DTG+3TC was evaluated in the randomized, phase 3 TANGO trial, which included 741 subjects who were already virally suppressed on a TAF-based three- or four-drug regimen. After 48 weeks of therapy, the two-drug regimen was noninferior to remaining on TAF-based therapy in terms of achieving and maintaining viral suppression, according to investigator Jean van Wyk, MB, ChB, Global Medical Lead for dolutegravir at ViiV Healthcare.

Safety outcomes were similar between the arms, though the absolute number of treatment-related adverse events was higher in the DTG+3TC arm “as expected in a switch study,” Dr. van Wyk said.

The percentage of subjects withdrawing from the study because of adverse events was 4% in the DTG+3TC arm and less than 1% in the TAF-based treatment arm, according to reported data.

And with regard to safety there were similar outcomes between the two arms, with regard to overall adverse events, “but as expected in a switch study, we did see more treatment-related adverse events in the dolutegravir plus lamivudine arm, and that’s because the majority of patients were on two new agents in the form of dolutegravir plus lamivudine, so it’s completely expected,” Dr. van Wyk said.

The study met its primary endpoint for noninferiority at week 48, based on the Food and Drug Administration snapshot algorithm. Results showed that switching to DTG+3TC was noninferior to continuing the TAF-containing regimen at week 48, with virologic failure per snapshot criteria seen in less than 1% of subjects in either arm, according to reported data. The proportion of subjects with plasma HIV-1 RNA less than 50 c/mL was 93.2% and 93.0% for the DTG+3TC and TAF-based treatment arms, respectively.

Longer-term follow-up will be important to confirm the noninferiority of the two-drug approach, Dr. van Wyk and Dr. Cahn said in the press conference. The TANGO study of the switch strategy will continue through 148 weeks, while an additional year of follow-up is ongoing for the GEMINI studies of the initial therapy approach.

TANGO and both GEMINI 1 and GEMINI 2 were sponsored by ViiV Healthcare. Dr. van Wyk is an employee of ViiV Healthcare. Dr. Cahn has received research support grants, and fees as consultant and speaker from ViiV Healthcare.

SOURCE: Cahn P et al. IAS 2019, Abstract WEAB0404LB; van Wyk J et al. IAS 2019, Abstract WEAB0403LB.

New studies of a two-drug, integrase inhibitor–based regimen, presented at the International AIDS Society Conference on HIV Science, provide additional data to challenge the three-drug HIV treatment paradigm.

In the results of one study, known as TANGO (NCT03446573), switching to the fixed-dose combination of dolutegravir (DTG) plus lamivudine (3TC) from a tenofovir alafenamide (TAF)–based three- or four-drug regimen maintained virologic suppression at 48 weeks in HIV-1 infected adults, an investigator said, and was noninferior to continuing TAF-based therapy.

In another presentation, updating results of the GEMINI-1 (NCT02831673) and GEMINI-2 studies (NCT02831764), a researcher said the DTG+3TC combination remained noninferior to DTG plus tenofovir/emtricitabine (TDF/FTC) at week 96 in antiretroviral (ART) treatment-naive adults with HIV-1 infection, with no treatment-emergent resistance and no increase in risk of virologic failure.

In light of these findings and encouraging findings from studies of other two-drug regimens, it may be time to “rethink the position of dual therapy in the international guidelines,” according to IAS Past President Pedro Cahn, MD, PhD, of Fundación Huésped, Buenos Aires, who presented the updated GEMINI study results.

“We don’t mean to say now everything should be dual therapy, and we are going to wipe out all other options, but I think we have another strong option for initiating therapy, and probably also for switch therapy,” Dr. Cahn said in a press conference.

Dr. Cahn presented an updated analysis of GEMINI-1 and GEMINI-2, two identically designed phase 3 randomized clinical trials including a total of 1,400 patients.

The 48-week results from those trials, presented in 2018, showed for the first time that a dual-therapy combination of an integrase inhibitor with 3TC was noninferior to the triple-drug regimen of DTG+TDF/FTC, Dr. Cahn said.

In the updated analysis, including 96 weeks of data, the two-drug regimen remained noninferior to the three-drug regimen, according to the investigator.

A total of 11 patients on DTG+3TC and 7 on DTG+TDF/FTC met virologic withdrawal criteria through week 96, with no treatment-emergent resistance mutations seen in either arm, according to results reported in the study abstract.

The proportion of subjects with plasma HIV-1 RNA below 50 c/mL at week 96 was 86% for the two-drug regimen and 90% for the three-drug regimen (adjusted difference, –3.4; 95% confidence interval, –6.7 to 0.0), the reported data showed.

Drug-related adverse events were numerically more common in the three-drug arm, though rates of adverse event–related withdrawal were low in both arms, according to investigators.

The strategy of switching to DTG+3TC was evaluated in the randomized, phase 3 TANGO trial, which included 741 subjects who were already virally suppressed on a TAF-based three- or four-drug regimen. After 48 weeks of therapy, the two-drug regimen was noninferior to remaining on TAF-based therapy in terms of achieving and maintaining viral suppression, according to investigator Jean van Wyk, MB, ChB, Global Medical Lead for dolutegravir at ViiV Healthcare.

Safety outcomes were similar between the arms, though the absolute number of treatment-related adverse events was higher in the DTG+3TC arm “as expected in a switch study,” Dr. van Wyk said.

The percentage of subjects withdrawing from the study because of adverse events was 4% in the DTG+3TC arm and less than 1% in the TAF-based treatment arm, according to reported data.

And with regard to safety there were similar outcomes between the two arms, with regard to overall adverse events, “but as expected in a switch study, we did see more treatment-related adverse events in the dolutegravir plus lamivudine arm, and that’s because the majority of patients were on two new agents in the form of dolutegravir plus lamivudine, so it’s completely expected,” Dr. van Wyk said.

The study met its primary endpoint for noninferiority at week 48, based on the Food and Drug Administration snapshot algorithm. Results showed that switching to DTG+3TC was noninferior to continuing the TAF-containing regimen at week 48, with virologic failure per snapshot criteria seen in less than 1% of subjects in either arm, according to reported data. The proportion of subjects with plasma HIV-1 RNA less than 50 c/mL was 93.2% and 93.0% for the DTG+3TC and TAF-based treatment arms, respectively.

Longer-term follow-up will be important to confirm the noninferiority of the two-drug approach, Dr. van Wyk and Dr. Cahn said in the press conference. The TANGO study of the switch strategy will continue through 148 weeks, while an additional year of follow-up is ongoing for the GEMINI studies of the initial therapy approach.

TANGO and both GEMINI 1 and GEMINI 2 were sponsored by ViiV Healthcare. Dr. van Wyk is an employee of ViiV Healthcare. Dr. Cahn has received research support grants, and fees as consultant and speaker from ViiV Healthcare.

SOURCE: Cahn P et al. IAS 2019, Abstract WEAB0404LB; van Wyk J et al. IAS 2019, Abstract WEAB0403LB.

In patients with previously untreated achalasia, peroral endoscopic myotomy had a high procedural success rate as compared to pneumatic dilation, results of a randomized clinical trial show.

Peroral endoscopic myotomy (POEM) had a success rate exceeding 90%, versus just about 50% for standard balloon dilation in what investigators say is, to their knowledge, the first-ever randomized trial to evaluate POEM as a first-line modality for this esophageal motility disorder.

Reflux esophagitis was the major downside of POEM, according to investigators, who reported the complication in 41% of patients at a 2-year follow-up, as compared to just 7% of patients undergoing the standard balloon dilation.

Nevertheless, there were no serious adverse events among 63 POEM-treated patients, while one patient out of 63 undergoing pneumatic dilation had a perforation that required endoscopic closure and hospitalization, according to senior study author Albert J. Bredenoord, MD, PhD, of Amsterdam University Medical Center.

“These findings support consideration of POEM as an initial treatment option for patients with achalasia,” Dr. Bredenoord and coinvestigators said in a report on the study appearing in JAMA.

While endoscopic pneumatic dilation is the usual treatment for achalasia, POEM has become more commonly used following case series showing high rates of efficacy, according to the authors.

The POEM procedure also offers advantages over laparoscopic Heller myotomy, which is invasive and associated with severe complications, including a transmural perforation rate of 4%-10%, they said in their report.

Their randomized trial included 133 adults with newly diagnosed achalasia enrolled at one of six hospitals in Germany, Hong Kong, Italy, Netherlands, and the United States.

Patients were randomly assigned to undergo 1-2 pneumatic dilations performed by an endoscopist who had performed at least 20 such procedures in the past, or to a POEM procedure likewise performed by an expert who had already done more than 20 such procedures.

At baseline, patients’ Eckardt symptom scores ranged from 6 to 9 on a scale with 0 indicating the lowest severity, to 12 indicating the highest. The median Eckardt scores were 8 in the POEM group and 7 in the pneumatic dilation group.

Treatment success, defined as an Eckardt score under 3 and no severe complications or retreatment at 2 years, was achieved by 58 of 63 patients (92%) in the POEM group, compared with 34 of 63 patients (54%) in the pneumatic dilation group (P less than .001), investigators reported.

Reflux esophagitis was observed in 22 of 54 POEM-treated patients (41%) who underwent endoscopy at a 2-year evaluation, compared with only 2 of 29 patients (7%) who had received the balloon dilation procedure (P = .002). In line with that finding, both reflux symptoms and daily proton pump inhibitor use were more common in the POEM group, investigators said.

However, there were no differences between POEM and pneumatic dilation groups in quality of life and other secondary endpoints, including median barium column height and median integrated relaxation pressure, they reported.

Two serious adverse events related to treatment were seen, according to investigators, including one perforation requiring an endoscopic closure plus antibiotics and hospitalization for 13 days, and one hospital admission for a night because of severe chest pain with no signs of perforation.

“Although POEM is more invasive and requires more technical endoscopic skills, the risk of severe complications was not higher than with pneumatic dilation, especially when performed by experienced endoscopists,” Dr. Bredenoord and coauthors said in their report.

However, these results do not imply that the traditional dilation procedure should be abandoned, they said, as POEM is more invasive, more involved, and more likely to result in reflux esophagitis.

“It seems reasonable to offer both options to treatment-naive patients with achalasia and counsel them to select treatment based on the patient’s characteristics, personal preference, comorbidity, and disease subtype,” they said.

Funding for the study came from Fonds NutsOhra and the European Society of Gastrointestinal Endoscopy. Dr. Bredenoord reported disclosures related to Norgine, Laborie, Medtronic, Diversatek, Nutricia, Regeneron, Celgene, Bayer, and Dr. Falk Pharma.

SOURCE: Ponds FA et al. JAMA. 2019;322(2):134-44. doi: 10.1001/jama.2019.8859.

In patients with previously untreated achalasia, peroral endoscopic myotomy had a high procedural success rate as compared to pneumatic dilation, results of a randomized clinical trial show.

Peroral endoscopic myotomy (POEM) had a success rate exceeding 90%, versus just about 50% for standard balloon dilation in what investigators say is, to their knowledge, the first-ever randomized trial to evaluate POEM as a first-line modality for this esophageal motility disorder.

Reflux esophagitis was the major downside of POEM, according to investigators, who reported the complication in 41% of patients at a 2-year follow-up, as compared to just 7% of patients undergoing the standard balloon dilation.

Nevertheless, there were no serious adverse events among 63 POEM-treated patients, while one patient out of 63 undergoing pneumatic dilation had a perforation that required endoscopic closure and hospitalization, according to senior study author Albert J. Bredenoord, MD, PhD, of Amsterdam University Medical Center.

“These findings support consideration of POEM as an initial treatment option for patients with achalasia,” Dr. Bredenoord and coinvestigators said in a report on the study appearing in JAMA.

While endoscopic pneumatic dilation is the usual treatment for achalasia, POEM has become more commonly used following case series showing high rates of efficacy, according to the authors.

The POEM procedure also offers advantages over laparoscopic Heller myotomy, which is invasive and associated with severe complications, including a transmural perforation rate of 4%-10%, they said in their report.

Their randomized trial included 133 adults with newly diagnosed achalasia enrolled at one of six hospitals in Germany, Hong Kong, Italy, Netherlands, and the United States.

Patients were randomly assigned to undergo 1-2 pneumatic dilations performed by an endoscopist who had performed at least 20 such procedures in the past, or to a POEM procedure likewise performed by an expert who had already done more than 20 such procedures.

At baseline, patients’ Eckardt symptom scores ranged from 6 to 9 on a scale with 0 indicating the lowest severity, to 12 indicating the highest. The median Eckardt scores were 8 in the POEM group and 7 in the pneumatic dilation group.

Treatment success, defined as an Eckardt score under 3 and no severe complications or retreatment at 2 years, was achieved by 58 of 63 patients (92%) in the POEM group, compared with 34 of 63 patients (54%) in the pneumatic dilation group (P less than .001), investigators reported.

Reflux esophagitis was observed in 22 of 54 POEM-treated patients (41%) who underwent endoscopy at a 2-year evaluation, compared with only 2 of 29 patients (7%) who had received the balloon dilation procedure (P = .002). In line with that finding, both reflux symptoms and daily proton pump inhibitor use were more common in the POEM group, investigators said.

However, there were no differences between POEM and pneumatic dilation groups in quality of life and other secondary endpoints, including median barium column height and median integrated relaxation pressure, they reported.

Two serious adverse events related to treatment were seen, according to investigators, including one perforation requiring an endoscopic closure plus antibiotics and hospitalization for 13 days, and one hospital admission for a night because of severe chest pain with no signs of perforation.

“Although POEM is more invasive and requires more technical endoscopic skills, the risk of severe complications was not higher than with pneumatic dilation, especially when performed by experienced endoscopists,” Dr. Bredenoord and coauthors said in their report.

However, these results do not imply that the traditional dilation procedure should be abandoned, they said, as POEM is more invasive, more involved, and more likely to result in reflux esophagitis.

“It seems reasonable to offer both options to treatment-naive patients with achalasia and counsel them to select treatment based on the patient’s characteristics, personal preference, comorbidity, and disease subtype,” they said.

Funding for the study came from Fonds NutsOhra and the European Society of Gastrointestinal Endoscopy. Dr. Bredenoord reported disclosures related to Norgine, Laborie, Medtronic, Diversatek, Nutricia, Regeneron, Celgene, Bayer, and Dr. Falk Pharma.

SOURCE: Ponds FA et al. JAMA. 2019;322(2):134-44. doi: 10.1001/jama.2019.8859.

In patients with previously untreated achalasia, peroral endoscopic myotomy had a high procedural success rate as compared to pneumatic dilation, results of a randomized clinical trial show.

Peroral endoscopic myotomy (POEM) had a success rate exceeding 90%, versus just about 50% for standard balloon dilation in what investigators say is, to their knowledge, the first-ever randomized trial to evaluate POEM as a first-line modality for this esophageal motility disorder.

Reflux esophagitis was the major downside of POEM, according to investigators, who reported the complication in 41% of patients at a 2-year follow-up, as compared to just 7% of patients undergoing the standard balloon dilation.

Nevertheless, there were no serious adverse events among 63 POEM-treated patients, while one patient out of 63 undergoing pneumatic dilation had a perforation that required endoscopic closure and hospitalization, according to senior study author Albert J. Bredenoord, MD, PhD, of Amsterdam University Medical Center.

“These findings support consideration of POEM as an initial treatment option for patients with achalasia,” Dr. Bredenoord and coinvestigators said in a report on the study appearing in JAMA.

While endoscopic pneumatic dilation is the usual treatment for achalasia, POEM has become more commonly used following case series showing high rates of efficacy, according to the authors.

The POEM procedure also offers advantages over laparoscopic Heller myotomy, which is invasive and associated with severe complications, including a transmural perforation rate of 4%-10%, they said in their report.

Their randomized trial included 133 adults with newly diagnosed achalasia enrolled at one of six hospitals in Germany, Hong Kong, Italy, Netherlands, and the United States.

Patients were randomly assigned to undergo 1-2 pneumatic dilations performed by an endoscopist who had performed at least 20 such procedures in the past, or to a POEM procedure likewise performed by an expert who had already done more than 20 such procedures.

At baseline, patients’ Eckardt symptom scores ranged from 6 to 9 on a scale with 0 indicating the lowest severity, to 12 indicating the highest. The median Eckardt scores were 8 in the POEM group and 7 in the pneumatic dilation group.

Treatment success, defined as an Eckardt score under 3 and no severe complications or retreatment at 2 years, was achieved by 58 of 63 patients (92%) in the POEM group, compared with 34 of 63 patients (54%) in the pneumatic dilation group (P less than .001), investigators reported.

Reflux esophagitis was observed in 22 of 54 POEM-treated patients (41%) who underwent endoscopy at a 2-year evaluation, compared with only 2 of 29 patients (7%) who had received the balloon dilation procedure (P = .002). In line with that finding, both reflux symptoms and daily proton pump inhibitor use were more common in the POEM group, investigators said.

However, there were no differences between POEM and pneumatic dilation groups in quality of life and other secondary endpoints, including median barium column height and median integrated relaxation pressure, they reported.

Two serious adverse events related to treatment were seen, according to investigators, including one perforation requiring an endoscopic closure plus antibiotics and hospitalization for 13 days, and one hospital admission for a night because of severe chest pain with no signs of perforation.

“Although POEM is more invasive and requires more technical endoscopic skills, the risk of severe complications was not higher than with pneumatic dilation, especially when performed by experienced endoscopists,” Dr. Bredenoord and coauthors said in their report.

However, these results do not imply that the traditional dilation procedure should be abandoned, they said, as POEM is more invasive, more involved, and more likely to result in reflux esophagitis.

“It seems reasonable to offer both options to treatment-naive patients with achalasia and counsel them to select treatment based on the patient’s characteristics, personal preference, comorbidity, and disease subtype,” they said.

Funding for the study came from Fonds NutsOhra and the European Society of Gastrointestinal Endoscopy. Dr. Bredenoord reported disclosures related to Norgine, Laborie, Medtronic, Diversatek, Nutricia, Regeneron, Celgene, Bayer, and Dr. Falk Pharma.

SOURCE: Ponds FA et al. JAMA. 2019;322(2):134-44. doi: 10.1001/jama.2019.8859.

The risk of neural tube defects linked to dolutegravir exposure during pregnancy is lower than previously signaled, according to new reports that have prompted the World Health Organization (WHO) to confirm that this antiviral medication should be the preferred option across all populations.

alexskopje/Thinkstock

The use of dolutegravir (DTG) during pregnancy has been a pressing global health question since May 2018, when an unplanned interim analysis of the Tsepamo surveillance study of birth outcomes in Botswana showed four neural tube defects associated with dolutegravir exposure among 426 infants born to HIV-positive women (0.94%).

With follow-up for additional births, however, just one more neural tube defect was identified out of 1,683 deliveries among women who had taken DTG around the time of conception (0.30%), according to a report just presented here at the at the International AIDS Society Conference on HIV Science.

By comparison, prevalence rates of neural tube defects were 0.10% for mothers taking other antiretroviral therapies at conception, 0.04% for those specifically taking efavirenz at conception, and 0.08% in HIV-uninfected mothers, according to the report, which was simultaneously published in the New England Journal of Medicine.

“While there may be a risk for neural tube defects, this risk is small, and really importantly, needs to be weighed against the large potential benefits of dolutegravir,” investigator Rebecca M. Zash, MD, of Beth Israel Deaconess Medical Center, Boston, said here in Mexico City during an IAS 2019 video press conference.

The WHO had previously sounded a note of caution, saying that DTG could be “considered” in women of childbearing age if other first‐line antiretroviral agents such as efavirenz could not be used.

However, following release of new evidence, including the study by Dr. Zash and colleagues, the WHO has come out with a clear recommendation for HIV drug as “the preferred first-line and second-line treatment for all populations, including pregnant women and those of childbearing potential.”

The updated scientific reports and guidelines have important implications for global health. “Many countries have been working to make dolutegravir-based treatment their preferred first-line regimen, as it’s got several advantages over efavirenz, which people have been using for many years now, including its tolerability and resistance profiles, and its impact on morbidity and mortality,” IAS president Anton Pozniak, MD, said in the press conference.

Some countries paused their plans to roll out dolutegravir-based regimens after the preliminary safety signal from the Tsepamo study was reported, Dr. Pozniak added.

In another study presented at IAS looking at dolutegravir use at conception, investigators described an additional surveillance study in Botswana, conducted independently from the Tsepamo study. One neural tube defect was found among 152 deliveries in mothers who had been taking DTG at conception (0.66%), and two neural tube defects among 2,326 deliveries to HIV-negative mothers (0.09%).

Although the number of deliveries are small in this study, the results suggest a risk of neural tube defects with DTG exposure at conception of less than 1%, said Mmakgomo Mimi Raesima, MD, MPH, public health specialist, Ministry of Health and Wellness, Botswana.

Because neural-tube defects might be related to low folate levels, Dr. Raesima said “conversations are continuing” with regard to folate food fortification in Botswana, a country that does not mandate folate-fortified grains.

“We want to capitalize on the momentum from these results,” Dr. Raesima said in the press conference.

The Tsepamo study was funded by the National Institutes of Health. Dr. Zash reported grants during the conduct of the study from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SOURCE: Zash R et al. N Engl J Med. 2019 Jul 22. doi: 10.1056/NEJMoa1905230.

The risk of neural tube defects linked to dolutegravir exposure during pregnancy is lower than previously signaled, according to new reports that have prompted the World Health Organization (WHO) to confirm that this antiviral medication should be the preferred option across all populations.

alexskopje/Thinkstock

The use of dolutegravir (DTG) during pregnancy has been a pressing global health question since May 2018, when an unplanned interim analysis of the Tsepamo surveillance study of birth outcomes in Botswana showed four neural tube defects associated with dolutegravir exposure among 426 infants born to HIV-positive women (0.94%).

With follow-up for additional births, however, just one more neural tube defect was identified out of 1,683 deliveries among women who had taken DTG around the time of conception (0.30%), according to a report just presented here at the at the International AIDS Society Conference on HIV Science.

By comparison, prevalence rates of neural tube defects were 0.10% for mothers taking other antiretroviral therapies at conception, 0.04% for those specifically taking efavirenz at conception, and 0.08% in HIV-uninfected mothers, according to the report, which was simultaneously published in the New England Journal of Medicine.

“While there may be a risk for neural tube defects, this risk is small, and really importantly, needs to be weighed against the large potential benefits of dolutegravir,” investigator Rebecca M. Zash, MD, of Beth Israel Deaconess Medical Center, Boston, said here in Mexico City during an IAS 2019 video press conference.

The WHO had previously sounded a note of caution, saying that DTG could be “considered” in women of childbearing age if other first‐line antiretroviral agents such as efavirenz could not be used.

However, following release of new evidence, including the study by Dr. Zash and colleagues, the WHO has come out with a clear recommendation for HIV drug as “the preferred first-line and second-line treatment for all populations, including pregnant women and those of childbearing potential.”

The updated scientific reports and guidelines have important implications for global health. “Many countries have been working to make dolutegravir-based treatment their preferred first-line regimen, as it’s got several advantages over efavirenz, which people have been using for many years now, including its tolerability and resistance profiles, and its impact on morbidity and mortality,” IAS president Anton Pozniak, MD, said in the press conference.

Some countries paused their plans to roll out dolutegravir-based regimens after the preliminary safety signal from the Tsepamo study was reported, Dr. Pozniak added.

In another study presented at IAS looking at dolutegravir use at conception, investigators described an additional surveillance study in Botswana, conducted independently from the Tsepamo study. One neural tube defect was found among 152 deliveries in mothers who had been taking DTG at conception (0.66%), and two neural tube defects among 2,326 deliveries to HIV-negative mothers (0.09%).

Although the number of deliveries are small in this study, the results suggest a risk of neural tube defects with DTG exposure at conception of less than 1%, said Mmakgomo Mimi Raesima, MD, MPH, public health specialist, Ministry of Health and Wellness, Botswana.

Because neural-tube defects might be related to low folate levels, Dr. Raesima said “conversations are continuing” with regard to folate food fortification in Botswana, a country that does not mandate folate-fortified grains.

“We want to capitalize on the momentum from these results,” Dr. Raesima said in the press conference.

The Tsepamo study was funded by the National Institutes of Health. Dr. Zash reported grants during the conduct of the study from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SOURCE: Zash R et al. N Engl J Med. 2019 Jul 22. doi: 10.1056/NEJMoa1905230.

The risk of neural tube defects linked to dolutegravir exposure during pregnancy is lower than previously signaled, according to new reports that have prompted the World Health Organization (WHO) to confirm that this antiviral medication should be the preferred option across all populations.

alexskopje/Thinkstock

The use of dolutegravir (DTG) during pregnancy has been a pressing global health question since May 2018, when an unplanned interim analysis of the Tsepamo surveillance study of birth outcomes in Botswana showed four neural tube defects associated with dolutegravir exposure among 426 infants born to HIV-positive women (0.94%).

With follow-up for additional births, however, just one more neural tube defect was identified out of 1,683 deliveries among women who had taken DTG around the time of conception (0.30%), according to a report just presented here at the at the International AIDS Society Conference on HIV Science.

By comparison, prevalence rates of neural tube defects were 0.10% for mothers taking other antiretroviral therapies at conception, 0.04% for those specifically taking efavirenz at conception, and 0.08% in HIV-uninfected mothers, according to the report, which was simultaneously published in the New England Journal of Medicine.

“While there may be a risk for neural tube defects, this risk is small, and really importantly, needs to be weighed against the large potential benefits of dolutegravir,” investigator Rebecca M. Zash, MD, of Beth Israel Deaconess Medical Center, Boston, said here in Mexico City during an IAS 2019 video press conference.

The WHO had previously sounded a note of caution, saying that DTG could be “considered” in women of childbearing age if other first‐line antiretroviral agents such as efavirenz could not be used.

However, following release of new evidence, including the study by Dr. Zash and colleagues, the WHO has come out with a clear recommendation for HIV drug as “the preferred first-line and second-line treatment for all populations, including pregnant women and those of childbearing potential.”

The updated scientific reports and guidelines have important implications for global health. “Many countries have been working to make dolutegravir-based treatment their preferred first-line regimen, as it’s got several advantages over efavirenz, which people have been using for many years now, including its tolerability and resistance profiles, and its impact on morbidity and mortality,” IAS president Anton Pozniak, MD, said in the press conference.

Some countries paused their plans to roll out dolutegravir-based regimens after the preliminary safety signal from the Tsepamo study was reported, Dr. Pozniak added.

In another study presented at IAS looking at dolutegravir use at conception, investigators described an additional surveillance study in Botswana, conducted independently from the Tsepamo study. One neural tube defect was found among 152 deliveries in mothers who had been taking DTG at conception (0.66%), and two neural tube defects among 2,326 deliveries to HIV-negative mothers (0.09%).

Although the number of deliveries are small in this study, the results suggest a risk of neural tube defects with DTG exposure at conception of less than 1%, said Mmakgomo Mimi Raesima, MD, MPH, public health specialist, Ministry of Health and Wellness, Botswana.

Because neural-tube defects might be related to low folate levels, Dr. Raesima said “conversations are continuing” with regard to folate food fortification in Botswana, a country that does not mandate folate-fortified grains.

“We want to capitalize on the momentum from these results,” Dr. Raesima said in the press conference.

The Tsepamo study was funded by the National Institutes of Health. Dr. Zash reported grants during the conduct of the study from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SOURCE: Zash R et al. N Engl J Med. 2019 Jul 22. doi: 10.1056/NEJMoa1905230.

Colorectal cancer (CRC) incidence continues to rise in younger adults, with no signs of plateauing, according to investigators who recently conducted an analysis of a large US cancer registry.

Adults aged 50 years and younger accounted for about 12% of colorectal cancer diagnoses in 2015, up from 10% in 2004, and significantly more of those younger patients had advanced disease at diagnosis as compared to older adults, according to the analysis of the National Cancer Database (NCDB) by Boone Goodgame, MD, of the University of Texas at Austin, and colleagues.

“These results may provide support for adjusting CRC screening guidelines to identify patients before the age of 50 years,” said Dr. Goodgame and study coauthors in Cancer.

Only 5.8% of colorectal cancer cases were diagnosed in individuals younger than 45 years, suggesting that age may be an “appropriate target” for the screening age, the authors said in their report, alluding to the 2018 qualified recommendation from the American Cancer Society to begin screening at age 45.

However, a member of the U.S. Preventive Services Task Force – which continues to recommend screening of asymptomatic adults starting at 50 years – said in an editorial that it remains “unknown” whether the harms of screening for sporadic cases of colorectal cancer in younger individuals would outweigh the benefits.

The study by Dr. Goodgame and colleagues included a total of 1,185,763 colorectal cancer cases in the NCDB during 2004-2015, of which 89% were diagnosed at the age of 50 or older, and 11% were diagnosed in younger individuals.

The proportion of colorectal cancer cases diagnosed in people aged 50 years and younger increased from 10.0% to 12.2% during the study period (P less than .0001), with comparable increases for both rectal and colon primary tumors, according to the the journal article.

Younger patients were more likely to have stage III and stage IV disease than older patients were, according to the investigators. Stage III disease was reported for 28.1% and 23.1% of younger individuals and those over 50 years, respectively, while stage IV disease was reported for 23.5% and 16.9% (P less than .0001 for both comparisons).

Race and sex differences were seen in proportions of patients younger than 50 years with colorectal cancer, further analysis of the NCDB data showed.

Among men, only non-Hispanic whites had a significant increase in colorectal cancer diagnoses under the age of 50 years over the study period, while in women, significant increases were seen in Hispanic and non-Hispanic whites, according to the report.

It’s unclear exactly what’s behind the increase in colorectal cancer diagnosis, the authors acknowledged in their report, citing a host of potentially explanatory factors, such as access to health care, lifestyle factors such as obesity, or increased antibiotic use.

Some say the increase could simply be from the more liberal use of colonoscopy, resulting in a lead time bias, the authors noted.

“However, a change in the lead-time bias should also increase the proportion of earlier stage disease in younger adults, and we did not see this in our study,” they said in the report. “Therefore, increasing colonoscopy use does not appear to be a sufficient explanation for this association.”

In any case, more studies are needed to better determine the risks, benefits, and costs of screening individuals younger than 50 years for colorectal cancer, they concluded, saying that their data should be included in an “ongoing discussion” of screening guidelines.

Dr. Goodgame and coauthors made no conflict of interest disclosures related to the study, which was supported by the National Cancer Institute and the Cancer Prevention and Research Institute of Texas.

SOURCE: Virostko J et al. Cancer. 2019 Jul 22. doi: 10.1002/cncr.32347.

Colorectal cancer (CRC) incidence continues to rise in younger adults, with no signs of plateauing, according to investigators who recently conducted an analysis of a large US cancer registry.

Adults aged 50 years and younger accounted for about 12% of colorectal cancer diagnoses in 2015, up from 10% in 2004, and significantly more of those younger patients had advanced disease at diagnosis as compared to older adults, according to the analysis of the National Cancer Database (NCDB) by Boone Goodgame, MD, of the University of Texas at Austin, and colleagues.

“These results may provide support for adjusting CRC screening guidelines to identify patients before the age of 50 years,” said Dr. Goodgame and study coauthors in Cancer.

Only 5.8% of colorectal cancer cases were diagnosed in individuals younger than 45 years, suggesting that age may be an “appropriate target” for the screening age, the authors said in their report, alluding to the 2018 qualified recommendation from the American Cancer Society to begin screening at age 45.

However, a member of the U.S. Preventive Services Task Force – which continues to recommend screening of asymptomatic adults starting at 50 years – said in an editorial that it remains “unknown” whether the harms of screening for sporadic cases of colorectal cancer in younger individuals would outweigh the benefits.

The study by Dr. Goodgame and colleagues included a total of 1,185,763 colorectal cancer cases in the NCDB during 2004-2015, of which 89% were diagnosed at the age of 50 or older, and 11% were diagnosed in younger individuals.

The proportion of colorectal cancer cases diagnosed in people aged 50 years and younger increased from 10.0% to 12.2% during the study period (P less than .0001), with comparable increases for both rectal and colon primary tumors, according to the the journal article.

Younger patients were more likely to have stage III and stage IV disease than older patients were, according to the investigators. Stage III disease was reported for 28.1% and 23.1% of younger individuals and those over 50 years, respectively, while stage IV disease was reported for 23.5% and 16.9% (P less than .0001 for both comparisons).

Race and sex differences were seen in proportions of patients younger than 50 years with colorectal cancer, further analysis of the NCDB data showed.

Among men, only non-Hispanic whites had a significant increase in colorectal cancer diagnoses under the age of 50 years over the study period, while in women, significant increases were seen in Hispanic and non-Hispanic whites, according to the report.

It’s unclear exactly what’s behind the increase in colorectal cancer diagnosis, the authors acknowledged in their report, citing a host of potentially explanatory factors, such as access to health care, lifestyle factors such as obesity, or increased antibiotic use.

Some say the increase could simply be from the more liberal use of colonoscopy, resulting in a lead time bias, the authors noted.

“However, a change in the lead-time bias should also increase the proportion of earlier stage disease in younger adults, and we did not see this in our study,” they said in the report. “Therefore, increasing colonoscopy use does not appear to be a sufficient explanation for this association.”

In any case, more studies are needed to better determine the risks, benefits, and costs of screening individuals younger than 50 years for colorectal cancer, they concluded, saying that their data should be included in an “ongoing discussion” of screening guidelines.

Dr. Goodgame and coauthors made no conflict of interest disclosures related to the study, which was supported by the National Cancer Institute and the Cancer Prevention and Research Institute of Texas.

SOURCE: Virostko J et al. Cancer. 2019 Jul 22. doi: 10.1002/cncr.32347.

Colorectal cancer (CRC) incidence continues to rise in younger adults, with no signs of plateauing, according to investigators who recently conducted an analysis of a large US cancer registry.

Adults aged 50 years and younger accounted for about 12% of colorectal cancer diagnoses in 2015, up from 10% in 2004, and significantly more of those younger patients had advanced disease at diagnosis as compared to older adults, according to the analysis of the National Cancer Database (NCDB) by Boone Goodgame, MD, of the University of Texas at Austin, and colleagues.

“These results may provide support for adjusting CRC screening guidelines to identify patients before the age of 50 years,” said Dr. Goodgame and study coauthors in Cancer.

Only 5.8% of colorectal cancer cases were diagnosed in individuals younger than 45 years, suggesting that age may be an “appropriate target” for the screening age, the authors said in their report, alluding to the 2018 qualified recommendation from the American Cancer Society to begin screening at age 45.

However, a member of the U.S. Preventive Services Task Force – which continues to recommend screening of asymptomatic adults starting at 50 years – said in an editorial that it remains “unknown” whether the harms of screening for sporadic cases of colorectal cancer in younger individuals would outweigh the benefits.

The study by Dr. Goodgame and colleagues included a total of 1,185,763 colorectal cancer cases in the NCDB during 2004-2015, of which 89% were diagnosed at the age of 50 or older, and 11% were diagnosed in younger individuals.

The proportion of colorectal cancer cases diagnosed in people aged 50 years and younger increased from 10.0% to 12.2% during the study period (P less than .0001), with comparable increases for both rectal and colon primary tumors, according to the the journal article.

Younger patients were more likely to have stage III and stage IV disease than older patients were, according to the investigators. Stage III disease was reported for 28.1% and 23.1% of younger individuals and those over 50 years, respectively, while stage IV disease was reported for 23.5% and 16.9% (P less than .0001 for both comparisons).

Race and sex differences were seen in proportions of patients younger than 50 years with colorectal cancer, further analysis of the NCDB data showed.

Among men, only non-Hispanic whites had a significant increase in colorectal cancer diagnoses under the age of 50 years over the study period, while in women, significant increases were seen in Hispanic and non-Hispanic whites, according to the report.

It’s unclear exactly what’s behind the increase in colorectal cancer diagnosis, the authors acknowledged in their report, citing a host of potentially explanatory factors, such as access to health care, lifestyle factors such as obesity, or increased antibiotic use.

Some say the increase could simply be from the more liberal use of colonoscopy, resulting in a lead time bias, the authors noted.

“However, a change in the lead-time bias should also increase the proportion of earlier stage disease in younger adults, and we did not see this in our study,” they said in the report. “Therefore, increasing colonoscopy use does not appear to be a sufficient explanation for this association.”

In any case, more studies are needed to better determine the risks, benefits, and costs of screening individuals younger than 50 years for colorectal cancer, they concluded, saying that their data should be included in an “ongoing discussion” of screening guidelines.

Dr. Goodgame and coauthors made no conflict of interest disclosures related to the study, which was supported by the National Cancer Institute and the Cancer Prevention and Research Institute of Texas.

SOURCE: Virostko J et al. Cancer. 2019 Jul 22. doi: 10.1002/cncr.32347.

Both systolic and diastolic hypertension independently predict myocardial infarction and strokes, but systolic blood pressure is more strongly linked to adverse outcomes.

That’s according to a study of more than 1 million patients and 36 million outpatient blood pressure measurements published in the New England Journal of Medicine.

Systolic and diastolic hypertension predicted adverse outcomes at cutpoints of 140/90 and 130/80 mm Hg in the large retrospective cohort study, supporting the recent guideline changes that made blood pressure targets more stringent for higher-risk patients, said lead investigator Alexander C. Flint, MD, of Kaiser Permanente Northern California (KPNC) in Oakland.

“While systolic does count for more, in the fact that it is a stronger driver of the risk of heart attack and stroke, diastolic absolutely does as well, and it does so independently. So we ignore our diastolic hypertension at our own peril,” Dr. Flint said in an interview.

Systolic hypertension began to overshadow diastolic after the Framingham Heart Study and others that suggested it is a more important predictor of adverse cardiovascular outcomes, Dr. Flint and coauthors said in a report on their study.

Those findings caused some to say diastole should be abandoned, and led to a “near-exclusive focus” on systolic hypertension in a 2000 advisory statement from the National High Blood Pressure Education Program, they say in their report.

While current guidelines emphasize the importance of both systolic and diastolic targets, many clinicians today often assign little importance to diastolic blood pressure values, the report adds.

“The pendulum needs to swing back, right down in the middle,” Dr. Flint said in the interview.

The study by Dr. Flint and colleagues comprised a cohort of approximately 1.3 million outpatients from KPNC who had at least one baseline blood pressure reading in during 2007-2008, and two or more follow-up measurements between 2009 and 2016, for a total of about 36.8 million data points.

Systolic hypertension burden was linked to the composite of MI or stroke, with a hazard ratio of 1.18 (95% confidence interval, 1.17-1.18; P less than .001) per unit increase in z score, according to results of a multivariable regression analysis. Likewise, diastolic hypertension burden was linked to those adverse outcomes, with a hazard ratio of 1.06 (95% CI, 1.06-1.07; P less than .001).

Put in terms of estimated risk of MI or stroke, patients with a systolic blood pressure around 160 mm Hg – 3 standard deviations from the mean – was 4.8%, compared to a predicted risk of just 1.9% for a systolic blood pressure near 136 mm Hg, the investigators said in their report.

Similarly, predicted risk was 3.6% for a diastolic pressure of about 96 mm Hg, also 3 standard deviations from the mean, and 1.9% for a diastolic BP near 81 mm Hg.

“The two are not that separate,” Dr. Flint said of the risks associated with systolic and diastolic hypertension at that 3-standard-deviation point. Beyond that, increased systolic blood pressure is associated with more risk relative to increased diastolic blood pressure, the logistic regression modeling shows.

Taken together, findings from this large cohort study emphasize the importance of making lifestyle modifications and adjusting medication to ensure that both systolic and diastolic targets are met, according to Dr. Flint.

“Rises in systolic blood pressure count for more in influencing the risk of heart attack and stroke,” he said, “but diastolic independently counts for quite a lot. It’s a close second.”

Dr. Flint reported no disclosures. Senior author Deepak L. Bhatt, MD, MPH, reported disclosures with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Takeda, The Medicines Company, and others. The remaining authors had no disclosures.

SOURCE: Flint AC et al. N Engl J Med. 2019 Jul 18. doi: 10.1056/NEJMoa1803180.

Both systolic and diastolic hypertension independently predict myocardial infarction and strokes, but systolic blood pressure is more strongly linked to adverse outcomes.

That’s according to a study of more than 1 million patients and 36 million outpatient blood pressure measurements published in the New England Journal of Medicine.

Systolic and diastolic hypertension predicted adverse outcomes at cutpoints of 140/90 and 130/80 mm Hg in the large retrospective cohort study, supporting the recent guideline changes that made blood pressure targets more stringent for higher-risk patients, said lead investigator Alexander C. Flint, MD, of Kaiser Permanente Northern California (KPNC) in Oakland.

“While systolic does count for more, in the fact that it is a stronger driver of the risk of heart attack and stroke, diastolic absolutely does as well, and it does so independently. So we ignore our diastolic hypertension at our own peril,” Dr. Flint said in an interview.

Systolic hypertension began to overshadow diastolic after the Framingham Heart Study and others that suggested it is a more important predictor of adverse cardiovascular outcomes, Dr. Flint and coauthors said in a report on their study.

Those findings caused some to say diastole should be abandoned, and led to a “near-exclusive focus” on systolic hypertension in a 2000 advisory statement from the National High Blood Pressure Education Program, they say in their report.

While current guidelines emphasize the importance of both systolic and diastolic targets, many clinicians today often assign little importance to diastolic blood pressure values, the report adds.

“The pendulum needs to swing back, right down in the middle,” Dr. Flint said in the interview.

The study by Dr. Flint and colleagues comprised a cohort of approximately 1.3 million outpatients from KPNC who had at least one baseline blood pressure reading in during 2007-2008, and two or more follow-up measurements between 2009 and 2016, for a total of about 36.8 million data points.

Systolic hypertension burden was linked to the composite of MI or stroke, with a hazard ratio of 1.18 (95% confidence interval, 1.17-1.18; P less than .001) per unit increase in z score, according to results of a multivariable regression analysis. Likewise, diastolic hypertension burden was linked to those adverse outcomes, with a hazard ratio of 1.06 (95% CI, 1.06-1.07; P less than .001).

Put in terms of estimated risk of MI or stroke, patients with a systolic blood pressure around 160 mm Hg – 3 standard deviations from the mean – was 4.8%, compared to a predicted risk of just 1.9% for a systolic blood pressure near 136 mm Hg, the investigators said in their report.

Similarly, predicted risk was 3.6% for a diastolic pressure of about 96 mm Hg, also 3 standard deviations from the mean, and 1.9% for a diastolic BP near 81 mm Hg.

“The two are not that separate,” Dr. Flint said of the risks associated with systolic and diastolic hypertension at that 3-standard-deviation point. Beyond that, increased systolic blood pressure is associated with more risk relative to increased diastolic blood pressure, the logistic regression modeling shows.

Taken together, findings from this large cohort study emphasize the importance of making lifestyle modifications and adjusting medication to ensure that both systolic and diastolic targets are met, according to Dr. Flint.

“Rises in systolic blood pressure count for more in influencing the risk of heart attack and stroke,” he said, “but diastolic independently counts for quite a lot. It’s a close second.”

Dr. Flint reported no disclosures. Senior author Deepak L. Bhatt, MD, MPH, reported disclosures with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Takeda, The Medicines Company, and others. The remaining authors had no disclosures.

SOURCE: Flint AC et al. N Engl J Med. 2019 Jul 18. doi: 10.1056/NEJMoa1803180.

Both systolic and diastolic hypertension independently predict myocardial infarction and strokes, but systolic blood pressure is more strongly linked to adverse outcomes.

That’s according to a study of more than 1 million patients and 36 million outpatient blood pressure measurements published in the New England Journal of Medicine.

Systolic and diastolic hypertension predicted adverse outcomes at cutpoints of 140/90 and 130/80 mm Hg in the large retrospective cohort study, supporting the recent guideline changes that made blood pressure targets more stringent for higher-risk patients, said lead investigator Alexander C. Flint, MD, of Kaiser Permanente Northern California (KPNC) in Oakland.

“While systolic does count for more, in the fact that it is a stronger driver of the risk of heart attack and stroke, diastolic absolutely does as well, and it does so independently. So we ignore our diastolic hypertension at our own peril,” Dr. Flint said in an interview.

Systolic hypertension began to overshadow diastolic after the Framingham Heart Study and others that suggested it is a more important predictor of adverse cardiovascular outcomes, Dr. Flint and coauthors said in a report on their study.

Those findings caused some to say diastole should be abandoned, and led to a “near-exclusive focus” on systolic hypertension in a 2000 advisory statement from the National High Blood Pressure Education Program, they say in their report.

While current guidelines emphasize the importance of both systolic and diastolic targets, many clinicians today often assign little importance to diastolic blood pressure values, the report adds.

“The pendulum needs to swing back, right down in the middle,” Dr. Flint said in the interview.

The study by Dr. Flint and colleagues comprised a cohort of approximately 1.3 million outpatients from KPNC who had at least one baseline blood pressure reading in during 2007-2008, and two or more follow-up measurements between 2009 and 2016, for a total of about 36.8 million data points.

Systolic hypertension burden was linked to the composite of MI or stroke, with a hazard ratio of 1.18 (95% confidence interval, 1.17-1.18; P less than .001) per unit increase in z score, according to results of a multivariable regression analysis. Likewise, diastolic hypertension burden was linked to those adverse outcomes, with a hazard ratio of 1.06 (95% CI, 1.06-1.07; P less than .001).

Put in terms of estimated risk of MI or stroke, patients with a systolic blood pressure around 160 mm Hg – 3 standard deviations from the mean – was 4.8%, compared to a predicted risk of just 1.9% for a systolic blood pressure near 136 mm Hg, the investigators said in their report.

Similarly, predicted risk was 3.6% for a diastolic pressure of about 96 mm Hg, also 3 standard deviations from the mean, and 1.9% for a diastolic BP near 81 mm Hg.

“The two are not that separate,” Dr. Flint said of the risks associated with systolic and diastolic hypertension at that 3-standard-deviation point. Beyond that, increased systolic blood pressure is associated with more risk relative to increased diastolic blood pressure, the logistic regression modeling shows.

Taken together, findings from this large cohort study emphasize the importance of making lifestyle modifications and adjusting medication to ensure that both systolic and diastolic targets are met, according to Dr. Flint.

“Rises in systolic blood pressure count for more in influencing the risk of heart attack and stroke,” he said, “but diastolic independently counts for quite a lot. It’s a close second.”

Dr. Flint reported no disclosures. Senior author Deepak L. Bhatt, MD, MPH, reported disclosures with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, Takeda, The Medicines Company, and others. The remaining authors had no disclosures.

SOURCE: Flint AC et al. N Engl J Med. 2019 Jul 18. doi: 10.1056/NEJMoa1803180.

Obese children and adolescents with multiple sclerosis (MS) had twice as many relapses on first-line treatment as compared with their non-obese counterparts, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.

The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.

“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.

This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.

Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.

This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.

Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90^th percentile, according to the report.

Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.

A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.

Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).

Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.

“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.

Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.

SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997

Obese children and adolescents with multiple sclerosis (MS) had twice as many relapses on first-line treatment as compared with their non-obese counterparts, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.

The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.

“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.

This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.

Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.

This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.

Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90^th percentile, according to the report.

Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.

A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.

Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).

Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.

“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.

Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.

SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997

Obese children and adolescents with multiple sclerosis (MS) had twice as many relapses on first-line treatment as compared with their non-obese counterparts, results of a recent large, single-center study show. The rate of switching to second-line disease-modifying therapy was consequently about 50% higher among the obese children in the study, which included a total of 453 pediatric patients.

The link between obesity and treatment response suggests that the management of these younger patients with MS could be improved through weight loss or body mass index (BMI)-adjusted dosing, according to Peter Huppke, MD, of Georg August University in Göttingen, Germany, and co-investigators.

“The findings do not indicate that obesity promotes greater disease activity, but pharmacokinetic factors are more likely associated with treatment response,” Dr. Huppke and co-authors said in a report on their study, which was published online ahead of print July 15 in JAMA Neurology.

This is believed to be the first-ever study to find an association between BMI and treatment response in pediatric patients with MS, according to the authors, who said they also confirmed a link between obesity and MS.

Specifically, obesity increased MS susceptibility by two-fold as compared with healthy controls, a finding that they said adds to a small but growing body of evidence that high BMI is associated with increased risk of the disease in these younger individuals.

This retrospective study included 453 pediatric patients with MS treated at the Center for MS in Childhood and Adolescence in Göttingen, Germany between 1990 and 2016. About two-thirds were female and the mean age at MS diagnosis was about 14 years.

Of those patients, 126 (27.8%) were classified as obese based on a BMI greater than the 90^th percentile, according to the report.

Dr. Huppke and co-investigators found that high BMI was linked to a significantly increased odds of pediatric MS, with odds ratios of 2.19 (95% CI, 1.5-3.1; P < 0.001) in girls and 2.14 (95% CI, 1.3-3.5; P = 0.003) in boys.

A total of 277 of these pediatric patients received a first-line disease-modifying therapy for 6 months or longer, including 249 treated with interferon beta and 51 treated with glatiramer.

Relapses were more common in obese patients, according to the report. with an annualized relapse rate of 1.29, compared to just 0.72 for those who were not overweight (P < 0.001).

Consequently, likelihood of receiving a second-line treatment was about 1.5 times higher in the obese or extremely obese patients, investigators said.

“A healthy weight may potentially optimize treatment outcomes and reduce disease-related burden and health care costs,” they concluded in the report, adding that BMI-adjusted dosing may “increase the value” of first-line disease-modifying therapies.

Dr. Huppke reported disclosures related to Bayer Health Care, Merck Serono, and Novartis not associated with the current study.

SOURCE: Huppke B, et al. JAMA Neurol. 2019 Jul 15. doi: 10.1001/jamaneurol.2019.1997

For primary care patients with acute exacerbations of chronic obstructive pulmonary disease (COPD), point-of-care C-reactive protein testing reduced antibiotic use with no evidence of harm, according to a recent randomized, controlled trial.

Point-of-care C-reactive protein (CRP) testing led to fewer antibiotic prescriptions at the initial consultation, according to investigators participating in the PACE study, a multicenter, open-label trial of more than 600 patients with COPD enrolled at one of 86 general practices in the United Kingdom.

Patient-reported antibiotic use over the next 4 weeks was more than 20 percentage points lower for the group managed with the point-of-care strategy, compared with those who received usual care, according to the investigators, led by Christopher C. Butler, FMedSci, of the Nuffield Department of Primary Care Health Sciences at the University of Oxford (England).

Less antibiotic use and fewer prescriptions did not compromise patient-reported, disease-specific quality of life, added Dr. Butler and colleagues. Their report appears in the New England Journal of Medicine.

In the United States and in Europe, more than 80% of COPD patients with acute exacerbations will receive an antibiotic prescription, according to Dr. Butler and coauthors.

“Although many patients who have acute exacerbations of COPD are helped by these treatments, others are not,” wrote the investigators, noting that in one hospital-based study, about one in five such exacerbations were thought to be due to noninfectious causes.

The present study included patients at least 40 years of age who presented to a primary care practice with an acute exacerbation and at least one of the three Anthonisen criteria (increased dyspnea, sputum production, and sputum purulence) intended to guide antibiotic therapy in COPD. A total of 325 were randomly assigned to the CRP testing group, and 324 to a group that received just usual care.

Antibiotic use was reported by fewer patients in the CRP testing group, compared with the usual-care group (57.0% vs. 77.4%; adjusted odds ratio, 0.31, 95% confidence interval, 0.20-0.47), the investigators reported.

Only 47.7% of patients in the CRP-guided group received antibiotic prescriptions at the initial consultation, vs. 69.7% of patients in the usual care group.

Hospitalizations over 6 months of follow-up were reported for 8.6% and 9.3% of patients in the CRP-guided and usual-care groups, respectively, while diagnoses of pneumonia were recorded for 3.0% and 4.0%. There was no clinically important difference between groups in the rate of antibiotic-related adverse effects.

“The evidence from our trial suggests that CRP-guided antibiotic prescribing for COPD exacerbations in primary care clinics may reduce patient-reported use of antibiotics and the prescribing of antibiotics by clinicians,” Dr. Butler and colleagues said in a discussion of these results.

Findings from the study by Dr. Butler and colleagues are “compelling enough” to support C-reactive protein (CRP) testing to guide antibiotic use in patient who have acute exacerbations of COPD, wrote the authors of an accompanying editorial.

“The trial achieved its objective, which was to show that CRP testing safely reduces antibiotic use,” stated Allan S. Brett, MD, and Majdi N. Al-Hasan, MB,BS, of the department of medicine at the University of South Carolina, Columbia.

Point-of-care testing of CRP could be applied even more broadly in clinical practice, Dr. Brett and Dr. Al-Hasan wrote, since testing has been shown to reduce prescribing of antibiotics for suspected lower respiratory tract infections and other common presentations in patients with no COPD.

“Whether primary care practices in the United States would embrace point-of-care CRP testing is another matter, given the regulatory requirements for in-office laboratory testing and uncertainty about reimbursement,” they noted.

Reduced antibiotic prescribing in patients with COPD likely has certain benefits, including reducing risk of Clostridioides difficile colitis, according to the authors.

By contrast, the current study did not determine which COPD patients might benefit from antibiotics, if any, nor which antibiotic might be warranted for those patients.

The study was supported by the Health Technology Assessment Program of the UK National Institute for Health Research. Dr. Butler reported disclosures related to Roche Molecular Systems and Roche Molecular Diagnostics, among others.

SOURCE: Butler CC et al. N Engl J Med. 2019 Jul 10;381:111-20. doi: 10.1056/NEJMoa1803185.

For primary care patients with acute exacerbations of chronic obstructive pulmonary disease (COPD), point-of-care C-reactive protein testing reduced antibiotic use with no evidence of harm, according to a recent randomized, controlled trial.

Point-of-care C-reactive protein (CRP) testing led to fewer antibiotic prescriptions at the initial consultation, according to investigators participating in the PACE study, a multicenter, open-label trial of more than 600 patients with COPD enrolled at one of 86 general practices in the United Kingdom.

Patient-reported antibiotic use over the next 4 weeks was more than 20 percentage points lower for the group managed with the point-of-care strategy, compared with those who received usual care, according to the investigators, led by Christopher C. Butler, FMedSci, of the Nuffield Department of Primary Care Health Sciences at the University of Oxford (England).

Less antibiotic use and fewer prescriptions did not compromise patient-reported, disease-specific quality of life, added Dr. Butler and colleagues. Their report appears in the New England Journal of Medicine.

In the United States and in Europe, more than 80% of COPD patients with acute exacerbations will receive an antibiotic prescription, according to Dr. Butler and coauthors.

“Although many patients who have acute exacerbations of COPD are helped by these treatments, others are not,” wrote the investigators, noting that in one hospital-based study, about one in five such exacerbations were thought to be due to noninfectious causes.

The present study included patients at least 40 years of age who presented to a primary care practice with an acute exacerbation and at least one of the three Anthonisen criteria (increased dyspnea, sputum production, and sputum purulence) intended to guide antibiotic therapy in COPD. A total of 325 were randomly assigned to the CRP testing group, and 324 to a group that received just usual care.

Antibiotic use was reported by fewer patients in the CRP testing group, compared with the usual-care group (57.0% vs. 77.4%; adjusted odds ratio, 0.31, 95% confidence interval, 0.20-0.47), the investigators reported.

Only 47.7% of patients in the CRP-guided group received antibiotic prescriptions at the initial consultation, vs. 69.7% of patients in the usual care group.

Hospitalizations over 6 months of follow-up were reported for 8.6% and 9.3% of patients in the CRP-guided and usual-care groups, respectively, while diagnoses of pneumonia were recorded for 3.0% and 4.0%. There was no clinically important difference between groups in the rate of antibiotic-related adverse effects.

“The evidence from our trial suggests that CRP-guided antibiotic prescribing for COPD exacerbations in primary care clinics may reduce patient-reported use of antibiotics and the prescribing of antibiotics by clinicians,” Dr. Butler and colleagues said in a discussion of these results.

Findings from the study by Dr. Butler and colleagues are “compelling enough” to support C-reactive protein (CRP) testing to guide antibiotic use in patient who have acute exacerbations of COPD, wrote the authors of an accompanying editorial.

“The trial achieved its objective, which was to show that CRP testing safely reduces antibiotic use,” stated Allan S. Brett, MD, and Majdi N. Al-Hasan, MB,BS, of the department of medicine at the University of South Carolina, Columbia.

Point-of-care testing of CRP could be applied even more broadly in clinical practice, Dr. Brett and Dr. Al-Hasan wrote, since testing has been shown to reduce prescribing of antibiotics for suspected lower respiratory tract infections and other common presentations in patients with no COPD.

“Whether primary care practices in the United States would embrace point-of-care CRP testing is another matter, given the regulatory requirements for in-office laboratory testing and uncertainty about reimbursement,” they noted.

Reduced antibiotic prescribing in patients with COPD likely has certain benefits, including reducing risk of Clostridioides difficile colitis, according to the authors.

By contrast, the current study did not determine which COPD patients might benefit from antibiotics, if any, nor which antibiotic might be warranted for those patients.

The study was supported by the Health Technology Assessment Program of the UK National Institute for Health Research. Dr. Butler reported disclosures related to Roche Molecular Systems and Roche Molecular Diagnostics, among others.

SOURCE: Butler CC et al. N Engl J Med. 2019 Jul 10;381:111-20. doi: 10.1056/NEJMoa1803185.

For primary care patients with acute exacerbations of chronic obstructive pulmonary disease (COPD), point-of-care C-reactive protein testing reduced antibiotic use with no evidence of harm, according to a recent randomized, controlled trial.

Point-of-care C-reactive protein (CRP) testing led to fewer antibiotic prescriptions at the initial consultation, according to investigators participating in the PACE study, a multicenter, open-label trial of more than 600 patients with COPD enrolled at one of 86 general practices in the United Kingdom.

Patient-reported antibiotic use over the next 4 weeks was more than 20 percentage points lower for the group managed with the point-of-care strategy, compared with those who received usual care, according to the investigators, led by Christopher C. Butler, FMedSci, of the Nuffield Department of Primary Care Health Sciences at the University of Oxford (England).

Less antibiotic use and fewer prescriptions did not compromise patient-reported, disease-specific quality of life, added Dr. Butler and colleagues. Their report appears in the New England Journal of Medicine.

In the United States and in Europe, more than 80% of COPD patients with acute exacerbations will receive an antibiotic prescription, according to Dr. Butler and coauthors.

“Although many patients who have acute exacerbations of COPD are helped by these treatments, others are not,” wrote the investigators, noting that in one hospital-based study, about one in five such exacerbations were thought to be due to noninfectious causes.

The present study included patients at least 40 years of age who presented to a primary care practice with an acute exacerbation and at least one of the three Anthonisen criteria (increased dyspnea, sputum production, and sputum purulence) intended to guide antibiotic therapy in COPD. A total of 325 were randomly assigned to the CRP testing group, and 324 to a group that received just usual care.

Antibiotic use was reported by fewer patients in the CRP testing group, compared with the usual-care group (57.0% vs. 77.4%; adjusted odds ratio, 0.31, 95% confidence interval, 0.20-0.47), the investigators reported.

Only 47.7% of patients in the CRP-guided group received antibiotic prescriptions at the initial consultation, vs. 69.7% of patients in the usual care group.

Hospitalizations over 6 months of follow-up were reported for 8.6% and 9.3% of patients in the CRP-guided and usual-care groups, respectively, while diagnoses of pneumonia were recorded for 3.0% and 4.0%. There was no clinically important difference between groups in the rate of antibiotic-related adverse effects.

“The evidence from our trial suggests that CRP-guided antibiotic prescribing for COPD exacerbations in primary care clinics may reduce patient-reported use of antibiotics and the prescribing of antibiotics by clinicians,” Dr. Butler and colleagues said in a discussion of these results.

Findings from the study by Dr. Butler and colleagues are “compelling enough” to support C-reactive protein (CRP) testing to guide antibiotic use in patient who have acute exacerbations of COPD, wrote the authors of an accompanying editorial.

“The trial achieved its objective, which was to show that CRP testing safely reduces antibiotic use,” stated Allan S. Brett, MD, and Majdi N. Al-Hasan, MB,BS, of the department of medicine at the University of South Carolina, Columbia.

Point-of-care testing of CRP could be applied even more broadly in clinical practice, Dr. Brett and Dr. Al-Hasan wrote, since testing has been shown to reduce prescribing of antibiotics for suspected lower respiratory tract infections and other common presentations in patients with no COPD.

“Whether primary care practices in the United States would embrace point-of-care CRP testing is another matter, given the regulatory requirements for in-office laboratory testing and uncertainty about reimbursement,” they noted.

Reduced antibiotic prescribing in patients with COPD likely has certain benefits, including reducing risk of Clostridioides difficile colitis, according to the authors.

By contrast, the current study did not determine which COPD patients might benefit from antibiotics, if any, nor which antibiotic might be warranted for those patients.

The study was supported by the Health Technology Assessment Program of the UK National Institute for Health Research. Dr. Butler reported disclosures related to Roche Molecular Systems and Roche Molecular Diagnostics, among others.

SOURCE: Butler CC et al. N Engl J Med. 2019 Jul 10;381:111-20. doi: 10.1056/NEJMoa1803185.