Video

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

[email protected]

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

[email protected]

AMSTERDAM – Over the past couple of years, integrase inhibitors have become the preferred anchor drug worldwide for HIV-treatment regimens. But in May 2018, researchers first reported an unexpected signal that one drug from the class, dolutegravir, showed a statistically significant link with an increased rate of neural-tube defects in neonates born to women in Botswana who had received dolutegravir at the time they conceived.

The data showed a 0.94% incidence of a neonate born with a neural-tube defect (NTD) among 426 HIV-infected women who were taking dolutegravir when they became pregnant. While this surprising finding remains preliminary because of limited number of women studied so far, and although the magnitude of the apparent effect fell somewhat after factoring in no further infants born with an NTD among 170 additional exposed women, the suggestion of an important teratogenic effect from dolutegravir led to a special session during the 22nd International AIDS Conference. The overwhelming consensus from this session seemed to be that the possible excess of NTDs linked with treatment with an integrase strand transfer inhibitor (INSTI) at the start of pregnancy was concerning enough to suggest caution and extra counseling for women of childbearing potential, but it was by no means a reason to derail the worldwide shift to the INSTI drug class as the core agent for treating HIV.

Mitchel L. Zoler/MDedge News

Rise of the INSTIs

The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.

Mitchel L. Zoler/MDedge News

Well before news of the NTD signal came out, the conference program featured a plenary talk from Pedro Cahn, MD, PhD, entitled “Moving into the Integrase Era.” During his talk, Dr. Cahn proclaimed that HIV treatment is “moving toward the integrase world,” and recently featured “unprecedented rollout” in low-income countries. In addition to dolutegravir (Tivicay) the INSTI class includes raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Symtuza).

Dr. Cahn attributed the first-line status of the INSTIs to several factors: their higher antiviral activity, compared with every other anti-HIV drug including proven superior efficacy to efavirenz (Sustiva) – the former core drug for antiretroviral regimens, rapid viral suppression, good tolerability with a low rate of treatment discontinuations, good recovery of CD4 cells, a relatively high genetic barrier to selection of HIV resistance mutations with relatively few resistant mutations seen when used in combination regimen’s in treatment-naive patients, and few drug-drug interactions, By mid-2018, dolutegravir or another INSTI had been named part of a first-line HIV treatment regimen by several countries and by the World Health Organization; according to WHO data, by mid-2018 more than half the low- and middle-income countries of the world had endorsed an INSTI-containing regimen including Botswana, Brazil, Kenya, Nigeria, and Uganda, said Dr. Cahn, scientific director of the Huésbed Foundation in Buenos Aires.

Mitchel L. Zoler/MDedge News

One example of the success that dolutegravir has recently shown as first-line treatment came in data reported at the Conference from Brazil. where a three-drug regimen containing dolutegravir plus lamivudine (3TC; Epivir) and tenofovir (TDF; Viread) replaced a triple regimen of efavirenz plus 3TC and TDF as recommended first-line treatment in 2017. Data collected by the Brazilian Ministry of Health during January 2014-June 2017 identified 103,240 people at least 15 years old who received treatment for HIV. The review showed that 85% of people treated with a dolutegravir-containing regimen had successful viral suppression to an undetectable level, compared with 78% of people on the same regimen but with efavirenz instead of dolutegravir, Mariana V. Meireles reported at the conference. Other triple-drug regimens had even lower rates of viral suppression. After researchers controlled for the age, sex, level of adherence, and baseline viral load and CD4 cell count the people who received the dolutegravir-containing regimen had at least a 42% higher rate of undetectable virus compared with any other regimen used by Brazilian patients, said Ms. Meireles, a researcher with the Brazilian Ministry of Health in Brasilia.

Dr. Cahn acknowledged the current concern and uncertainty about INSTIs and NTDs. “Caution and effective contraception are recommended for dolutegravir. The risks and benefits should be compared with other [treatment] options. Women have the right to make informed choices,” he said. Dr. Cahn also highlighted that safety analyses need data from additional early-pregnancy exposures to clearly rule in or rule out a teratogenic effect from dolutegravir. And he stressed that, whether or not the possible NTD link is a class effect remains to be assessed as data from early-pregnancy exposures of women on other INSTIs are currently much more limited than they are those for dolutegravir. He also raised a question voiced by others: Is the effect from dolutegravir somehow mediated by folic acid levels, a dietary component that protects against NTDs? Botswana, the country that generated the NTD data, doesn’t fortify wheat flour or any other food with folic acid, as occurs in the United States, noted Rebecca M. Zash, MD, the researcher who led the Botswana study.

The NTD data

The signal for an NTD link to dolutegravir came from a study run in Botswana designed for a totally different, albeit related purpose. The Tsepamo study launched in 2014 with the goal of assessing the safety of efavirenz-based HIV regimens when used by pregnant women. The study has run at eight of the country’s largest maternity wards, where nearly half of Botswana’s deliveries occur. The midwives at those locations collected data on all women at their clinics, and once Botswana adopted dolutegravir as its anchor drug of choice for treating people infected with HIV in 2017 significant numbers of the women in the Tsepamo study received dolutegravir. Through May 1, 2018, the study had enrolled more than 89,000 women who had 88,755 live births, including nearly 22,000 women infected with HIV (and more than 66,000 without infection), nearly 12,00 of those infected with HIV who received some type of antiretroviral therapy, 5,787 on efavirenz at the time of conception, 2,812 women who started on dolutegravir treatment during pregnancy, and 426 women who were on dolutegravir at the time of conception, said Dr. Zash, an infectious diseases physician at Beth Israel Deaconess Hospital in Boston and codirector of the Reproductive Health for HIV-Infected Populations Study Working Group at the Harvard University Center for AIDS Research in Cambridge, Mass.

Mitchel L. Zoler/MDedge News

A recently published analysis by Dr. Zash and her associates found no difference in the incidence rate of adverse birth outcomes among women who started on either efavirenz or dolutegravir during pregnancy. This analysis also showed that women infected with HIV overall had “mildly increased” rates of both total adverse birth outcomes and severe adverse birth outcomes compared with women without HIV infection (Lancet Glob Health. 2018 Jul;6[7]:e804-e10).

When the researchers looked at NTDs among neonates born to women exposed at conception, they saw a different picture. The entire cohort of nearly 89,000 live births included 86 neonates with an NTD, a 0.1% rate. This included 4 of the 426 births from mothers on dolutegravir at conception, a 0.94% rate, significantly higher than the overall rate. Other comparator NTD rates included a 0,12% incidence among mothers on any anti-HIV drug other than dolutegravir at conception, a 0.09% rate among mothers who were not infected with HIV, and a 0.05% rate among mothers on efavirenz at conception, Dr. Zash and her associates reported in a publication that appeared coincident with her talk at the conference (N Engl J Med. 2018 Jul 24.doi: 10.1056/NEJMc1807653). The NTDs linked with dolutegravir use involved four distinct types of NTD, a finding Dr. Zash called “unusual,” but not unique among teratogens.

During her talk, Dr. Zash further updated the dolutegravir numbers based on extended follow-up of the Botswana cohort during May 1-July 15, during which time two NTDs occurred, one involving an uninfected mother and the second from a mother who started on dolutegravir at 8 weeks’ gestational age, after the time when NTDs occur. Further follow-up also added 170 more neonates born to women exposed to dolutegravir at conception, bringing the total now to 596 births with 4 NTDs or a rate of 0.67%, still significantly elevated, compared with other exposure groups. The Tsepamo study continues, with an additional 10 sites planned to soon join that will boost maternity coverage to 72% of Botswana’s annual births. The next planned analysis is in March 2019, and by then the number of neonates born to women with early dolutegravir exposure should more than double, Dr. Zash predicted.

Modeling the risks and benefits

Identifying a possible excess of NTDs with dolutegravir treatment in adolescent girls and young women doesn’t, of course, tell the whole risk-benefit story for dolutegravir and possibly the other INSTIs. Caitlin Dugdale, MD, an infectious diseases physician at Massachusetts General Hospital in Boston, reported a model she developed to better define the pluses and minuses of dolutegravir treatment, compared with efavirenz. The model used projections for women in South Africa of child-bearing potential infected by HIV over the next 5 years and used data on drug efficacy and harms based on published reports. For example, the ability of the two drugs to produce undetectable viral loads was assumed by the model to be 94% after 48 weeks on treatment with dolutegravir and 86% with efavirenz, based on the rates reported in the phase 3, randomized comparison of dolutegravir- and efavirenz-based regimens in the SINGLE trial, with adjustments for factors such as protocol deviations and mortality that were accounted for in other parts of the model, Dr. Dugdale said. She used estimates for NTD incidence based on the published numbers reported by Dr. Zash.

Mitchel L. Zoler/MDedge News

The results showed that, over the next 5 years, based on just the existing and projected rates of HIV infection, treating all infected women and children with a dolutegravir-based regimen instead of a regimen anchored by efavirenz would result in the benefits of 28,400 fewer deaths among women, 52,800 fewer sexual transmissions of HIV, 5,000 fewer pediatric HIV transmissions, and 1,600 fewer pediatric deaths unrelated to an NTD. On the minus side relying on dolutegravir instead of efavirenz was projected to cause an excess of 10,000 neonates born with an NTD, 8,400 excess pediatric deaths, and overall 5,400 fewer children alive and free from HIV. These projections were based on 3.5 million women on first-line treatment with antiretroviral therapy and 1.1 million children born with HIV exposure.

Dr. Dugdale drew particular attention to the comparison between 28,400 fewer deaths among women when treated with dolutegravir at the cost of 8,400 excess pediatric deaths, but cautioned that this creates “a difficult trade-off to balance.” Findings from the model and other information on HIV treatment options should enter into the decision making of each HIV-infected woman who could become pregnant, she said. It’s important that patients view the risks and benefits not just on a population level but on an individual, personal level, Dr. Dugdale said in a video interview. “The individual woman must balance the risks and benefits for herself and her child.”

“Patients need to decide what is important to them,” agreed Dr. Zash during the conference.

The NTD findings also underscored the importance of better contraception options for HIV-infected women. “This is an opportunity to improve reproductive health and contraception for women, especially in resource-poor countries,” commented Elaine J. Abrams, MD, professor of epidemiology and pediatrics at Columbia University in New York, who cochaired the conference session.

Another lesson from the NTD findings is the importance of tracking the safety of new drugs used when women become pregnant and during pregnancy. The dolutegravir arm of the Tsepamo study “was almost by accident,” noted the Georgetown medical ethicist, Dr. Little. “Every new treatment should be examined in pregnant women and infants,” she added. “Studies like this should not be left to chance. Women deserve an evidence base for medication use across the lifespan including during pregnancy and periconception.”

Dr. Little, Ms. Meireles, Dr. Zash, and Dr. Dugdale had no disclosures. Dr. Cahn has been an adviser to or speaker for AbbVie, Merck, and ViiV and has received research funding from AbbVie, Merck, ViiV, and Richmond. Dr. Abrams has been an adviser to Merck and ViiV. Viiv is the company that markets dolutegravir.
 

[email protected]

Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.

Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.

In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.

That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.

Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.

Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.

Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.

In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.

That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.

Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.

Contrary to what might be expected, chimeric antigen receptor (CAR) T cells with stronger signaling capabilities were less effective against lymphoma cells in a mouse model, investigators reported.

Intracellular signaling strength was a key determinant of T cell fate in the study, which was published in the journal Science Signaling.

By contrast, CAR signaling pathways could not be predicted solely by the costimulatory domains used to construct the receptor, investigators said.

Based on those findings, tailoring CAR design based on signal strength might improve the efficacy and reduce the toxicity of CAR T-cell therapy, according to Alexander Salter, an MD/PhD student at Fred Hutchinson Cancer Research Center, Seattle, Wash.

In a press conference, Mr. Salter described results of the study, which used mass spectrometry to evaluate CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells.

While CARs with CD28 domains elicited more robust intracellular signaling than those with 4-1BB domains, there was considerable overlap in activation of T cell signaling pathways, Mr. Salter said.

That overlap was somewhat surprising, according to Mr. Salter, since researchers have generally assumed that CARs with CD28 and 4-1BB costimulatory domains will primarily signal through those respective pathways.

“No matter what costimulatory domain was encoded by the receptor, both CARs… activated both CD28 and 41BB signaling pathways,” Mr. Salter said.

The major determinant of efficacy in the study turned out to be not the domain used to construct the receptor, but the speed and strength of signaling, he added. In particular, the CARs that evoked stronger signals also had increased T cell dysfunction, decreasing their potency in the mouse lymphoma model.

The T cells with a CD28 CAR had very strong initial antitumor function that quickly waned in the mouse model of lymphoma; by contrast, the “slower burning” 4-1BB CAR signal led to T cells that better retained their function in vivo and were associated with longer median survival in the model, he said.

Those findings suggest tailoring CAR design based on signal strength may improve clinical efficacy and reduce toxicity.

As part of the study, Mr. Salter and his co-investigators were able to modify the CAR CD28 domain to make the signaling of the CD28 CARs less intense. “This is a modification that we think should be considered in future CAR design,” Mr. Salter said.

While the alterations in the CD28 signaling domain were able to reduce levels of cytokines produced by T cells, the study was primarily designed to look at the efficacy, noted Stanley Riddell, MD, scientific director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center.

“Our models were not set up to address the question of toxicity, so we can’t directly say this would translate to what we would see in patients,” Dr. Riddell said during the press conference. “But I think we gleaned a lot of insights as to why cytokines are produced at greater or lesser levels with various CAR designs, and insights as to how to redesign these receptors to lower the levels of cytokines they make without compromising their ability to kill.”

Dr. Riddell is a founder, shareholder, and scientific advisor of Juno Therapeutics, and together with Mr. Salter, he has filed a patent application on the use of mutant CD28 CARs for cellular therapy. Co-author Raphael Gottardo, PhD, also with Fred Hutchinson Cancer Research Center, is a consultant for Juno Therapeutics. No other competing interests were reported.

SOURCE: Salter AI et al., Sci Signal. 2018 Aug 21;11. pii:eaat6753.

When Patrice Weiss, MD, was a resident, a healthy, low-risk patient underwent what should have been an uncomplicated vaginal hysterectomy. But the patient developed a series of postoperative complications leading to multisystem organ failure and a lengthy stay in intensive care.

“None of us could really figure out how this happened. I still can’t figure out how this person who was relatively young developed all these complications,” said Dr. Weiss, now chief medical officer of Carilion Clinic and professor of obstetrics and gynecology at Virginia Tech Carilion School of Medicine and Research Institute, both in Roanoke, Va. “There are times when you don’t know why something happened or what you could have done differently – and the answer may be nothing – but that dramatic, potentially very complicated outcome can really weigh on people. You still harbor those feelings of a second victim.”

It’s the health care professional who is that “second victim,” a term coined in 2000 by Albert W. Wu, MD, professor of public health at Johns Hopkins University, Baltimore, to describe an increasingly recognized phenomenon following unexpected adverse patient events, medical errors, or patient injuries (BMJ. 2000 Mar 18;320[7237]:726-7). The patients and their loved ones are the first victims, but a health care professional’s feelings of guilt, shame, inadequacy, and other powerful, complicated emotions can have long-lasting effects on his or her psyche, clinical practice, and career, particularly if he or she does not receive validation, support, and access to resources to work through the experience.

“Second victims ... become victimized in the sense that the provider is traumatized by the event,” Susan D. Scott, PhD, of the University of Missouri Health System, Columbia, and her colleagues wrote in a 2009 paper about the phenomenon (Qual Saf Health Care. 2009;18[5]:325-30). “Frequently, these individuals feel personally responsible for the patient outcome. Many feel as though they have failed the patient, second-guessing their clinical skills and knowledge base,” they said.

It’s that latter part that can fester and potentially poison a health care professional’s ability to function, according to Charlie Jaynes, MD, senior director of medical operations for Ob Hospitalist Group in Greenville, S.C.

“It makes you question yourself, and your treatment is not as well-defined and logical as it should be and therefore can have a direct effect on patient care and lead to poor outcomes,” Dr. Jaynes said. “It’s a very dangerous phenomenon because it can degrade the quality of medical care provided.”

Most physicians are trained to internalize and compartmentalize these experiences, to “suck it up and get on with it,” he said, but it’s now become clear that such a strategy can have disastrous professional and personal consequences.

“In the worst case scenario, people burn out, drop out or commit suicide, their marriage ends up in shambles, or they turn to drugs and alcohol,” Dr. Jaynes said. “What Dr. Wu did was open the box to allow some empathy and compassion to be introduced to the situation.”

Dangers of unaddressed second victim impact

Estimates vary widely on the prevalence of second victim phenomenon among physicians and nurses who have been involved in a medical error or unexpected serious outcome. Across the medical field, estimates range from 10% in a study among otolaryngologists (Laryngoscope. 2006 Jul;116[7]:1114-20) to up to 30% and 50% more broadly, although some fields may be more susceptible than others (Jt Comm J Qual Patient Saf. 2010;36[5]:233-40; BMJ Qual Saf. 2012;21[4]:267-70).

“In the world of obstetrics, we spend 99.9% of our time in a happy field of medicine filled with joy and new life,” Dr. Weiss said. “Whether consciously or unconsciously, those become the expectations of the patients and the providers, so when there is an outcome that is less than optimal, that’s when you’re even more affected because of what your expectations are going into it.”

Dr. Scott and her colleagues noted that the stages of being a second victim are similar to the Kübler-Ross stages:

• Stage 1: Chaos and event repair.
• Stage 2: Intrusive thoughts, “what if.”
• Stage 3: Restoring personal identity.
• Stage 4: Enduring the inquisition.
• Stage 5: Obtaining emotional first aid.
• Stage 6: Moving on or dropping out; surviving and/or thriving.”

“This can go on for years. Someone can spend years just surviving and not thriving,” Dr. Weiss said. “It can really happen along a continuum.”

Although studies have not looked specifically at second victims and patient care, research has shown that second victims have a higher risk of burnout, and that physicians with high burnout tend to order more tests, spend less time with patients, and have greater risk of making medical errors, Dr. Weiss said.

A study looking at the emotional impact of medical errors on physicians found that 61% had greater anxiety about making future medical errors, 44% had a loss of confidence, 42% had trouble sleeping, and 42% were less satisfied in their job (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).

“You have the risk of the provider leaving medicine altogether or significantly changing their practice patterns, or giving up obstetric care because of the emotional toll it takes on providers,” she said. “We already know that one of the crises facing medicine right now is burnout, so you have the risk of additional or worsening burnout.”
 

Recognizing the need for formal support programs

Research does clearly show a need for programs formally addressing these experiences. A 2007 survey found that only 10% of 3,171 of internal medicine doctors, pediatricians, family physicians, and surgeons felt their health care organizations provided adequate support in managing stress following a medical error, yet about 8 in 10 wanted support (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).

Organizations are responding. One of the first second-victim programs is the “forYOU” program implemented at the University of Missouri Health Care’s Office of Clinical Effectiveness in 2007. The free, 24-7 program provides a “safe zone” for expressing emotions and reactions confidentially.

Ob Hospitalist Group just launched the CARE (Clinician Assistance, Recovery & Encouragement) Program, the first national peer-support program for second victims. The first 25 volunteers who underwent training in September will serve the organization’s more than 700 health care professionals across 32 states.

Instead of psychological counseling or intervention, the program emphasizes active listening, nonjudgment, and compassion during confidential calls; peers don’t take notes or record the conversations.

“We will be quiet and listen and speak at the appropriate times to be compassionate and not make judgments,” Dr. Jaynes said. “I think its critical to realize that in order to do that you have to be one of us. If you haven’t been there yourself when a baby dies in utero or you have a mother almost die by hemorrhage or a complication of surgery ... it creates emotional turmoil. Everybody who’s worth their salt questions, ‘What did I do wrong?’ and we’re really harsh on ourselves. If I can say I realize it’s a horrible place to be because I’ve been there myself, I can be a useful peer.”

At Dr. Weiss’s institution, Carilion Clinic spent 5 years developing and implementing the TRUST second-victim program, emphasizing Treatment, Respect, Understanding/compassion, Supportive care, and Transparency. Dr. Weiss said the first step in developing such a program is talking about the problem.

“You need hospital leadership addressing the phenomenon of the second victim, recognizing it is real, that it’s not a sign of weakness for providers to have any of these signs,” she said. “It has to be done at an organizational level. There has to be a place where providers can talk freely about the emotional impact of the outcome, not just the clinical outcomes.”

Johns Hopkins Hospital in Baltimore published findings in September 2017 about its program RISE (Resilience In Stressful Events) (Jt Comm J Qual Patient Saf. 2017 Sep;43[9]:471-83 that was featured by the Joint Commission as a program that employs some of the tools the commission describes in its toolkit for health care organizations to develop second-victim support programs (Jt Comm J Qual Patient Saf. 2012 May;38[5]:235-40, 193).

It’s important that health care professionals are not expected or required to seek counseling or similar interventions, Dr. Weiss said, but they know of available resources.

“People need to be able to talk about it when they’re ready. It doesn’t necessarily matter how your peers judge your actions because these are feelings that come from within,” Dr. Weiss said, although colleagues can validate a second victim’s experience or feelings by sharing their own.

“It’s helpful when someone in a leadership role can acknowledge that this is real and say to a provider, ‘I’ve been there, and this is what helped me,’ or ‘I’ve been there, and there was no resource and I went without help for years,’ ” she said.

In fact, it’s her own past experiences that have made Dr. Weiss so passionate about raising awareness about second victims.

“I’ve been involved in cases of unanticipated outcomes and personally witnessed medical errors, and I’ve seen how very close colleagues can be affected,” she said. “This is a topic that really, really hits home for me.”
 

Signs and symptoms: How to recognize a possible second victim

Anyone can become a second victim, regardless of their training, experience, or years of practice, Dr. Weiss said. A health care professional may practice for years and witness many unanticipated poor outcomes before one suddenly drums up feelings they don’t expect.

“It’s almost inevitable that providers are going to have unanticipated outcomes or unexpected outcomes,” Dr. Weiss said. “The challenge with the second victim is no one can ever predict how someone is going to respond to an outcome, including ourselves. This may be the first time they have a response to something they never saw coming.”

Two aspects correlated with a higher risk of second victim are the severity of the morbidity or mortality of the patient and the degree of personal responsibility the health care professional feels. The signs and symptoms of being a second victim can be indistinguishable from those of depression, anxiety, or posttraumatic stress syndrome, but the biggest indicator is a change in a person’s normal behavior, Dr. Weiss said.

“The person who is never late to work is late to work. The person who is always mild-mannered is on edge,” she said. “A lot of it is subtle personality or behavior changes, or you begin to notice practice pattern differences, such as ordering a bunch of labs.”

Perhaps the providers are snapping at people when they’ve never snapped before, or they express more cynicism or sarcasm, she added. “A change in their sleeping or eating patterns or in their personal hygiene are all things that one could look for.”

According to Dr. Jaynes, emotional signs may include irritability, fear, anger, grief, remorse, frustration, desperation, numbness, guilt, loneliness, shock and feeling disconnected, feeling hopeless or out of control. Physical symptoms include headaches, muscle tension, chest pain, extreme fatigue, sleeping problems, appetite changes or gastrointestinal symptoms, dizziness, frequent illnesses, being easily startled, or increased heart rate, blood pressure, or breathing rate. Other possible signs include flashbacks, nightmares, social avoidance, difficulties concentrating, poor memory, avoiding patient care areas, fearing repercussions to their reputations, and decreased job satisfaction. Second victims also may experience a loss in confidence or spiritual connection, or loss of interest in work, usual activities, and connections with others.

Dr. Weiss and Dr. Jaynes said they had no relevant financial disclosures.

When Patrice Weiss, MD, was a resident, a healthy, low-risk patient underwent what should have been an uncomplicated vaginal hysterectomy. But the patient developed a series of postoperative complications leading to multisystem organ failure and a lengthy stay in intensive care.

“None of us could really figure out how this happened. I still can’t figure out how this person who was relatively young developed all these complications,” said Dr. Weiss, now chief medical officer of Carilion Clinic and professor of obstetrics and gynecology at Virginia Tech Carilion School of Medicine and Research Institute, both in Roanoke, Va. “There are times when you don’t know why something happened or what you could have done differently – and the answer may be nothing – but that dramatic, potentially very complicated outcome can really weigh on people. You still harbor those feelings of a second victim.”

It’s the health care professional who is that “second victim,” a term coined in 2000 by Albert W. Wu, MD, professor of public health at Johns Hopkins University, Baltimore, to describe an increasingly recognized phenomenon following unexpected adverse patient events, medical errors, or patient injuries (BMJ. 2000 Mar 18;320[7237]:726-7). The patients and their loved ones are the first victims, but a health care professional’s feelings of guilt, shame, inadequacy, and other powerful, complicated emotions can have long-lasting effects on his or her psyche, clinical practice, and career, particularly if he or she does not receive validation, support, and access to resources to work through the experience.

“Second victims ... become victimized in the sense that the provider is traumatized by the event,” Susan D. Scott, PhD, of the University of Missouri Health System, Columbia, and her colleagues wrote in a 2009 paper about the phenomenon (Qual Saf Health Care. 2009;18[5]:325-30). “Frequently, these individuals feel personally responsible for the patient outcome. Many feel as though they have failed the patient, second-guessing their clinical skills and knowledge base,” they said.

It’s that latter part that can fester and potentially poison a health care professional’s ability to function, according to Charlie Jaynes, MD, senior director of medical operations for Ob Hospitalist Group in Greenville, S.C.

“It makes you question yourself, and your treatment is not as well-defined and logical as it should be and therefore can have a direct effect on patient care and lead to poor outcomes,” Dr. Jaynes said. “It’s a very dangerous phenomenon because it can degrade the quality of medical care provided.”

Most physicians are trained to internalize and compartmentalize these experiences, to “suck it up and get on with it,” he said, but it’s now become clear that such a strategy can have disastrous professional and personal consequences.

“In the worst case scenario, people burn out, drop out or commit suicide, their marriage ends up in shambles, or they turn to drugs and alcohol,” Dr. Jaynes said. “What Dr. Wu did was open the box to allow some empathy and compassion to be introduced to the situation.”

Dangers of unaddressed second victim impact

Estimates vary widely on the prevalence of second victim phenomenon among physicians and nurses who have been involved in a medical error or unexpected serious outcome. Across the medical field, estimates range from 10% in a study among otolaryngologists (Laryngoscope. 2006 Jul;116[7]:1114-20) to up to 30% and 50% more broadly, although some fields may be more susceptible than others (Jt Comm J Qual Patient Saf. 2010;36[5]:233-40; BMJ Qual Saf. 2012;21[4]:267-70).

“In the world of obstetrics, we spend 99.9% of our time in a happy field of medicine filled with joy and new life,” Dr. Weiss said. “Whether consciously or unconsciously, those become the expectations of the patients and the providers, so when there is an outcome that is less than optimal, that’s when you’re even more affected because of what your expectations are going into it.”

Dr. Scott and her colleagues noted that the stages of being a second victim are similar to the Kübler-Ross stages:

• Stage 1: Chaos and event repair.
• Stage 2: Intrusive thoughts, “what if.”
• Stage 3: Restoring personal identity.
• Stage 4: Enduring the inquisition.
• Stage 5: Obtaining emotional first aid.
• Stage 6: Moving on or dropping out; surviving and/or thriving.”

“This can go on for years. Someone can spend years just surviving and not thriving,” Dr. Weiss said. “It can really happen along a continuum.”

Although studies have not looked specifically at second victims and patient care, research has shown that second victims have a higher risk of burnout, and that physicians with high burnout tend to order more tests, spend less time with patients, and have greater risk of making medical errors, Dr. Weiss said.

A study looking at the emotional impact of medical errors on physicians found that 61% had greater anxiety about making future medical errors, 44% had a loss of confidence, 42% had trouble sleeping, and 42% were less satisfied in their job (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).

“You have the risk of the provider leaving medicine altogether or significantly changing their practice patterns, or giving up obstetric care because of the emotional toll it takes on providers,” she said. “We already know that one of the crises facing medicine right now is burnout, so you have the risk of additional or worsening burnout.”
 

Recognizing the need for formal support programs

Research does clearly show a need for programs formally addressing these experiences. A 2007 survey found that only 10% of 3,171 of internal medicine doctors, pediatricians, family physicians, and surgeons felt their health care organizations provided adequate support in managing stress following a medical error, yet about 8 in 10 wanted support (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).

Organizations are responding. One of the first second-victim programs is the “forYOU” program implemented at the University of Missouri Health Care’s Office of Clinical Effectiveness in 2007. The free, 24-7 program provides a “safe zone” for expressing emotions and reactions confidentially.

Ob Hospitalist Group just launched the CARE (Clinician Assistance, Recovery & Encouragement) Program, the first national peer-support program for second victims. The first 25 volunteers who underwent training in September will serve the organization’s more than 700 health care professionals across 32 states.

Instead of psychological counseling or intervention, the program emphasizes active listening, nonjudgment, and compassion during confidential calls; peers don’t take notes or record the conversations.

“We will be quiet and listen and speak at the appropriate times to be compassionate and not make judgments,” Dr. Jaynes said. “I think its critical to realize that in order to do that you have to be one of us. If you haven’t been there yourself when a baby dies in utero or you have a mother almost die by hemorrhage or a complication of surgery ... it creates emotional turmoil. Everybody who’s worth their salt questions, ‘What did I do wrong?’ and we’re really harsh on ourselves. If I can say I realize it’s a horrible place to be because I’ve been there myself, I can be a useful peer.”

At Dr. Weiss’s institution, Carilion Clinic spent 5 years developing and implementing the TRUST second-victim program, emphasizing Treatment, Respect, Understanding/compassion, Supportive care, and Transparency. Dr. Weiss said the first step in developing such a program is talking about the problem.

“You need hospital leadership addressing the phenomenon of the second victim, recognizing it is real, that it’s not a sign of weakness for providers to have any of these signs,” she said. “It has to be done at an organizational level. There has to be a place where providers can talk freely about the emotional impact of the outcome, not just the clinical outcomes.”

Johns Hopkins Hospital in Baltimore published findings in September 2017 about its program RISE (Resilience In Stressful Events) (Jt Comm J Qual Patient Saf. 2017 Sep;43[9]:471-83 that was featured by the Joint Commission as a program that employs some of the tools the commission describes in its toolkit for health care organizations to develop second-victim support programs (Jt Comm J Qual Patient Saf. 2012 May;38[5]:235-40, 193).

It’s important that health care professionals are not expected or required to seek counseling or similar interventions, Dr. Weiss said, but they know of available resources.

“People need to be able to talk about it when they’re ready. It doesn’t necessarily matter how your peers judge your actions because these are feelings that come from within,” Dr. Weiss said, although colleagues can validate a second victim’s experience or feelings by sharing their own.

“It’s helpful when someone in a leadership role can acknowledge that this is real and say to a provider, ‘I’ve been there, and this is what helped me,’ or ‘I’ve been there, and there was no resource and I went without help for years,’ ” she said.

In fact, it’s her own past experiences that have made Dr. Weiss so passionate about raising awareness about second victims.

“I’ve been involved in cases of unanticipated outcomes and personally witnessed medical errors, and I’ve seen how very close colleagues can be affected,” she said. “This is a topic that really, really hits home for me.”
 

Signs and symptoms: How to recognize a possible second victim

Anyone can become a second victim, regardless of their training, experience, or years of practice, Dr. Weiss said. A health care professional may practice for years and witness many unanticipated poor outcomes before one suddenly drums up feelings they don’t expect.

“It’s almost inevitable that providers are going to have unanticipated outcomes or unexpected outcomes,” Dr. Weiss said. “The challenge with the second victim is no one can ever predict how someone is going to respond to an outcome, including ourselves. This may be the first time they have a response to something they never saw coming.”

Two aspects correlated with a higher risk of second victim are the severity of the morbidity or mortality of the patient and the degree of personal responsibility the health care professional feels. The signs and symptoms of being a second victim can be indistinguishable from those of depression, anxiety, or posttraumatic stress syndrome, but the biggest indicator is a change in a person’s normal behavior, Dr. Weiss said.

“The person who is never late to work is late to work. The person who is always mild-mannered is on edge,” she said. “A lot of it is subtle personality or behavior changes, or you begin to notice practice pattern differences, such as ordering a bunch of labs.”

Perhaps the providers are snapping at people when they’ve never snapped before, or they express more cynicism or sarcasm, she added. “A change in their sleeping or eating patterns or in their personal hygiene are all things that one could look for.”

According to Dr. Jaynes, emotional signs may include irritability, fear, anger, grief, remorse, frustration, desperation, numbness, guilt, loneliness, shock and feeling disconnected, feeling hopeless or out of control. Physical symptoms include headaches, muscle tension, chest pain, extreme fatigue, sleeping problems, appetite changes or gastrointestinal symptoms, dizziness, frequent illnesses, being easily startled, or increased heart rate, blood pressure, or breathing rate. Other possible signs include flashbacks, nightmares, social avoidance, difficulties concentrating, poor memory, avoiding patient care areas, fearing repercussions to their reputations, and decreased job satisfaction. Second victims also may experience a loss in confidence or spiritual connection, or loss of interest in work, usual activities, and connections with others.

Dr. Weiss and Dr. Jaynes said they had no relevant financial disclosures.

When Patrice Weiss, MD, was a resident, a healthy, low-risk patient underwent what should have been an uncomplicated vaginal hysterectomy. But the patient developed a series of postoperative complications leading to multisystem organ failure and a lengthy stay in intensive care.

“None of us could really figure out how this happened. I still can’t figure out how this person who was relatively young developed all these complications,” said Dr. Weiss, now chief medical officer of Carilion Clinic and professor of obstetrics and gynecology at Virginia Tech Carilion School of Medicine and Research Institute, both in Roanoke, Va. “There are times when you don’t know why something happened or what you could have done differently – and the answer may be nothing – but that dramatic, potentially very complicated outcome can really weigh on people. You still harbor those feelings of a second victim.”

It’s the health care professional who is that “second victim,” a term coined in 2000 by Albert W. Wu, MD, professor of public health at Johns Hopkins University, Baltimore, to describe an increasingly recognized phenomenon following unexpected adverse patient events, medical errors, or patient injuries (BMJ. 2000 Mar 18;320[7237]:726-7). The patients and their loved ones are the first victims, but a health care professional’s feelings of guilt, shame, inadequacy, and other powerful, complicated emotions can have long-lasting effects on his or her psyche, clinical practice, and career, particularly if he or she does not receive validation, support, and access to resources to work through the experience.

“Second victims ... become victimized in the sense that the provider is traumatized by the event,” Susan D. Scott, PhD, of the University of Missouri Health System, Columbia, and her colleagues wrote in a 2009 paper about the phenomenon (Qual Saf Health Care. 2009;18[5]:325-30). “Frequently, these individuals feel personally responsible for the patient outcome. Many feel as though they have failed the patient, second-guessing their clinical skills and knowledge base,” they said.

It’s that latter part that can fester and potentially poison a health care professional’s ability to function, according to Charlie Jaynes, MD, senior director of medical operations for Ob Hospitalist Group in Greenville, S.C.

“It makes you question yourself, and your treatment is not as well-defined and logical as it should be and therefore can have a direct effect on patient care and lead to poor outcomes,” Dr. Jaynes said. “It’s a very dangerous phenomenon because it can degrade the quality of medical care provided.”

Most physicians are trained to internalize and compartmentalize these experiences, to “suck it up and get on with it,” he said, but it’s now become clear that such a strategy can have disastrous professional and personal consequences.

“In the worst case scenario, people burn out, drop out or commit suicide, their marriage ends up in shambles, or they turn to drugs and alcohol,” Dr. Jaynes said. “What Dr. Wu did was open the box to allow some empathy and compassion to be introduced to the situation.”

Dangers of unaddressed second victim impact

Estimates vary widely on the prevalence of second victim phenomenon among physicians and nurses who have been involved in a medical error or unexpected serious outcome. Across the medical field, estimates range from 10% in a study among otolaryngologists (Laryngoscope. 2006 Jul;116[7]:1114-20) to up to 30% and 50% more broadly, although some fields may be more susceptible than others (Jt Comm J Qual Patient Saf. 2010;36[5]:233-40; BMJ Qual Saf. 2012;21[4]:267-70).

“In the world of obstetrics, we spend 99.9% of our time in a happy field of medicine filled with joy and new life,” Dr. Weiss said. “Whether consciously or unconsciously, those become the expectations of the patients and the providers, so when there is an outcome that is less than optimal, that’s when you’re even more affected because of what your expectations are going into it.”

Dr. Scott and her colleagues noted that the stages of being a second victim are similar to the Kübler-Ross stages:

• Stage 1: Chaos and event repair.
• Stage 2: Intrusive thoughts, “what if.”
• Stage 3: Restoring personal identity.
• Stage 4: Enduring the inquisition.
• Stage 5: Obtaining emotional first aid.
• Stage 6: Moving on or dropping out; surviving and/or thriving.”

“This can go on for years. Someone can spend years just surviving and not thriving,” Dr. Weiss said. “It can really happen along a continuum.”

Although studies have not looked specifically at second victims and patient care, research has shown that second victims have a higher risk of burnout, and that physicians with high burnout tend to order more tests, spend less time with patients, and have greater risk of making medical errors, Dr. Weiss said.

A study looking at the emotional impact of medical errors on physicians found that 61% had greater anxiety about making future medical errors, 44% had a loss of confidence, 42% had trouble sleeping, and 42% were less satisfied in their job (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).

“You have the risk of the provider leaving medicine altogether or significantly changing their practice patterns, or giving up obstetric care because of the emotional toll it takes on providers,” she said. “We already know that one of the crises facing medicine right now is burnout, so you have the risk of additional or worsening burnout.”
 

Recognizing the need for formal support programs

Research does clearly show a need for programs formally addressing these experiences. A 2007 survey found that only 10% of 3,171 of internal medicine doctors, pediatricians, family physicians, and surgeons felt their health care organizations provided adequate support in managing stress following a medical error, yet about 8 in 10 wanted support (Jt Comm J Qual Patient Saf. 2007;33[8]:467-76).

Organizations are responding. One of the first second-victim programs is the “forYOU” program implemented at the University of Missouri Health Care’s Office of Clinical Effectiveness in 2007. The free, 24-7 program provides a “safe zone” for expressing emotions and reactions confidentially.

Ob Hospitalist Group just launched the CARE (Clinician Assistance, Recovery & Encouragement) Program, the first national peer-support program for second victims. The first 25 volunteers who underwent training in September will serve the organization’s more than 700 health care professionals across 32 states.

Instead of psychological counseling or intervention, the program emphasizes active listening, nonjudgment, and compassion during confidential calls; peers don’t take notes or record the conversations.

“We will be quiet and listen and speak at the appropriate times to be compassionate and not make judgments,” Dr. Jaynes said. “I think its critical to realize that in order to do that you have to be one of us. If you haven’t been there yourself when a baby dies in utero or you have a mother almost die by hemorrhage or a complication of surgery ... it creates emotional turmoil. Everybody who’s worth their salt questions, ‘What did I do wrong?’ and we’re really harsh on ourselves. If I can say I realize it’s a horrible place to be because I’ve been there myself, I can be a useful peer.”

At Dr. Weiss’s institution, Carilion Clinic spent 5 years developing and implementing the TRUST second-victim program, emphasizing Treatment, Respect, Understanding/compassion, Supportive care, and Transparency. Dr. Weiss said the first step in developing such a program is talking about the problem.

“You need hospital leadership addressing the phenomenon of the second victim, recognizing it is real, that it’s not a sign of weakness for providers to have any of these signs,” she said. “It has to be done at an organizational level. There has to be a place where providers can talk freely about the emotional impact of the outcome, not just the clinical outcomes.”

Johns Hopkins Hospital in Baltimore published findings in September 2017 about its program RISE (Resilience In Stressful Events) (Jt Comm J Qual Patient Saf. 2017 Sep;43[9]:471-83 that was featured by the Joint Commission as a program that employs some of the tools the commission describes in its toolkit for health care organizations to develop second-victim support programs (Jt Comm J Qual Patient Saf. 2012 May;38[5]:235-40, 193).

It’s important that health care professionals are not expected or required to seek counseling or similar interventions, Dr. Weiss said, but they know of available resources.

“People need to be able to talk about it when they’re ready. It doesn’t necessarily matter how your peers judge your actions because these are feelings that come from within,” Dr. Weiss said, although colleagues can validate a second victim’s experience or feelings by sharing their own.

“It’s helpful when someone in a leadership role can acknowledge that this is real and say to a provider, ‘I’ve been there, and this is what helped me,’ or ‘I’ve been there, and there was no resource and I went without help for years,’ ” she said.

In fact, it’s her own past experiences that have made Dr. Weiss so passionate about raising awareness about second victims.

“I’ve been involved in cases of unanticipated outcomes and personally witnessed medical errors, and I’ve seen how very close colleagues can be affected,” she said. “This is a topic that really, really hits home for me.”
 

Signs and symptoms: How to recognize a possible second victim

Anyone can become a second victim, regardless of their training, experience, or years of practice, Dr. Weiss said. A health care professional may practice for years and witness many unanticipated poor outcomes before one suddenly drums up feelings they don’t expect.

“It’s almost inevitable that providers are going to have unanticipated outcomes or unexpected outcomes,” Dr. Weiss said. “The challenge with the second victim is no one can ever predict how someone is going to respond to an outcome, including ourselves. This may be the first time they have a response to something they never saw coming.”

Two aspects correlated with a higher risk of second victim are the severity of the morbidity or mortality of the patient and the degree of personal responsibility the health care professional feels. The signs and symptoms of being a second victim can be indistinguishable from those of depression, anxiety, or posttraumatic stress syndrome, but the biggest indicator is a change in a person’s normal behavior, Dr. Weiss said.

“The person who is never late to work is late to work. The person who is always mild-mannered is on edge,” she said. “A lot of it is subtle personality or behavior changes, or you begin to notice practice pattern differences, such as ordering a bunch of labs.”

Perhaps the providers are snapping at people when they’ve never snapped before, or they express more cynicism or sarcasm, she added. “A change in their sleeping or eating patterns or in their personal hygiene are all things that one could look for.”

According to Dr. Jaynes, emotional signs may include irritability, fear, anger, grief, remorse, frustration, desperation, numbness, guilt, loneliness, shock and feeling disconnected, feeling hopeless or out of control. Physical symptoms include headaches, muscle tension, chest pain, extreme fatigue, sleeping problems, appetite changes or gastrointestinal symptoms, dizziness, frequent illnesses, being easily startled, or increased heart rate, blood pressure, or breathing rate. Other possible signs include flashbacks, nightmares, social avoidance, difficulties concentrating, poor memory, avoiding patient care areas, fearing repercussions to their reputations, and decreased job satisfaction. Second victims also may experience a loss in confidence or spiritual connection, or loss of interest in work, usual activities, and connections with others.

Dr. Weiss and Dr. Jaynes said they had no relevant financial disclosures.

WASHINGTON – Currently available options for treating itch in patients with atopic dermatitis continue to be somewhat limited, but range from several topical agents to oral medications, including antihistamines and an oral antiemetic approved for preventing chemotherapy-related nausea and vomiting, Peter Lio, MD, said at a symposium presented by the Coalition United for Better Eczema Care (CUBE-C).

There are four basic areas of treatment, which Dr. Lio, a dermatologist at Northwestern University, Chicago, referred to as the “itch therapeutic ladder.” In a video interview at the meeting, he reviewed the treatments, starting with topical therapies, which include camphor and menthol, strontium-containing topicals, as well as “dilute bleach-type products” that seem to have some anti-inflammatory and anti-itch effects.

The next levels: oral medications – antihistamines, followed by “more intense” options that may carry more risks, such as the antidepressant mirtazapine, and aprepitant, a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting. Gabapentin and naltrexone can also be helpful for certain populations; all are used off-label, he pointed out.

Dr. Lio, formally trained in acupuncture, often uses alternative therapies as the fourth rung of the ladder. These include using a specific acupressure point, which he said “seems to give a little bit of relief.”

In the interview, he also discussed considerations in children with atopic dermatitis and exciting treatments in development, such as biologics that target “one of the master itch cytokines,” interleukin-31.

“Itch is such an important part of this disease because we know not only is it one of the key pieces that pushes the disease forward and keeps these cycles going, but also contributes a huge amount to the morbidity,” he said.

CUBE-C, established by the National Eczema Association (NEA), is a “network of cross-specialty leaders, patients and caregivers, constructing an educational curriculum based on standards of effective treatment and disease management,” according to the NEA.

The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Lio reported serving as a speaker, consultant, and/or advisor for companies developing and marketing atopic dermatitis therapies and products.

[email protected]

WASHINGTON – Currently available options for treating itch in patients with atopic dermatitis continue to be somewhat limited, but range from several topical agents to oral medications, including antihistamines and an oral antiemetic approved for preventing chemotherapy-related nausea and vomiting, Peter Lio, MD, said at a symposium presented by the Coalition United for Better Eczema Care (CUBE-C).

There are four basic areas of treatment, which Dr. Lio, a dermatologist at Northwestern University, Chicago, referred to as the “itch therapeutic ladder.” In a video interview at the meeting, he reviewed the treatments, starting with topical therapies, which include camphor and menthol, strontium-containing topicals, as well as “dilute bleach-type products” that seem to have some anti-inflammatory and anti-itch effects.

The next levels: oral medications – antihistamines, followed by “more intense” options that may carry more risks, such as the antidepressant mirtazapine, and aprepitant, a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting. Gabapentin and naltrexone can also be helpful for certain populations; all are used off-label, he pointed out.

Dr. Lio, formally trained in acupuncture, often uses alternative therapies as the fourth rung of the ladder. These include using a specific acupressure point, which he said “seems to give a little bit of relief.”

In the interview, he also discussed considerations in children with atopic dermatitis and exciting treatments in development, such as biologics that target “one of the master itch cytokines,” interleukin-31.

“Itch is such an important part of this disease because we know not only is it one of the key pieces that pushes the disease forward and keeps these cycles going, but also contributes a huge amount to the morbidity,” he said.

CUBE-C, established by the National Eczema Association (NEA), is a “network of cross-specialty leaders, patients and caregivers, constructing an educational curriculum based on standards of effective treatment and disease management,” according to the NEA.

The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Lio reported serving as a speaker, consultant, and/or advisor for companies developing and marketing atopic dermatitis therapies and products.

[email protected]

WASHINGTON – Currently available options for treating itch in patients with atopic dermatitis continue to be somewhat limited, but range from several topical agents to oral medications, including antihistamines and an oral antiemetic approved for preventing chemotherapy-related nausea and vomiting, Peter Lio, MD, said at a symposium presented by the Coalition United for Better Eczema Care (CUBE-C).

There are four basic areas of treatment, which Dr. Lio, a dermatologist at Northwestern University, Chicago, referred to as the “itch therapeutic ladder.” In a video interview at the meeting, he reviewed the treatments, starting with topical therapies, which include camphor and menthol, strontium-containing topicals, as well as “dilute bleach-type products” that seem to have some anti-inflammatory and anti-itch effects.

The next levels: oral medications – antihistamines, followed by “more intense” options that may carry more risks, such as the antidepressant mirtazapine, and aprepitant, a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting. Gabapentin and naltrexone can also be helpful for certain populations; all are used off-label, he pointed out.

Dr. Lio, formally trained in acupuncture, often uses alternative therapies as the fourth rung of the ladder. These include using a specific acupressure point, which he said “seems to give a little bit of relief.”

In the interview, he also discussed considerations in children with atopic dermatitis and exciting treatments in development, such as biologics that target “one of the master itch cytokines,” interleukin-31.

“Itch is such an important part of this disease because we know not only is it one of the key pieces that pushes the disease forward and keeps these cycles going, but also contributes a huge amount to the morbidity,” he said.

CUBE-C, established by the National Eczema Association (NEA), is a “network of cross-specialty leaders, patients and caregivers, constructing an educational curriculum based on standards of effective treatment and disease management,” according to the NEA.

The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Lio reported serving as a speaker, consultant, and/or advisor for companies developing and marketing atopic dermatitis therapies and products.

[email protected]

WASHINGTON – The National Eczema Association (NEA) has established the Coalition United for Better Eczema Care (CUBE-C) to provide practitioners with a resource for “trustworthy, up-to-date, state of the art” information on atopic dermatitis, with the goal of improving health outcomes, according to Julie Block, president and chief executive officer of the NEA.

In an interview at a symposium presented by CUBE-C, Ms. Block provided more information on CUBE-C, including how and why it started and what it can offer to dermatologists, as well as primary care physicians, who care for patients with atopic dermatitis. She said that the NEA convened dermatologists, allergists, immunologists, psychologists, nurse practitioners, physician assistants, and patients “to design a curriculum that provided an entire picture of the patient experience, so that we could go out and educate not only on the basics of eczema and atopic dermatitis for a variety of practitioners ... but also for the specialists who are now going to be engaging in new innovations and new therapies for their patients.”

She was joined by Adam Friedman, MD, professor of dermatology and residency program director at George Washington University, Washington, where the symposium, a resident’s boot camp, was held. The boot camp was somewhat unique in that it was geared more towards trainees; typically, the CUBE-C program is a CME program for practitioners, but this reflects the flexibility of the program, which can be tailored to the audience, Dr. Friedman pointed out. “The hope is that programs like these pop up all over the place ... anywhere you have a critical mass of individuals who want to learn about this,” where planners can choose from a menu of topics provided by CUBE-C – which include therapeutics, infections, pathogenesis, and access to care – and “easily formulate a conference like we held here today for the right audience.”

Topics covered at the George Washington University symposium included the impact of climate on the prevalence of childhood eczema, the diagnosis and differential diagnosis in children, infections in atopic dermatitis patients, and itch treatment.

More information on CUBE-C is available on the NEA website.

The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Friedman reported serving as a speaker for Regeneron, Pfizer, and other companies. He also consults and serves on the advisory board for Pfizer and multiple other companies developing and marketing atopic dermatitis therapies and products.
 

[email protected]

WASHINGTON – The National Eczema Association (NEA) has established the Coalition United for Better Eczema Care (CUBE-C) to provide practitioners with a resource for “trustworthy, up-to-date, state of the art” information on atopic dermatitis, with the goal of improving health outcomes, according to Julie Block, president and chief executive officer of the NEA.

In an interview at a symposium presented by CUBE-C, Ms. Block provided more information on CUBE-C, including how and why it started and what it can offer to dermatologists, as well as primary care physicians, who care for patients with atopic dermatitis. She said that the NEA convened dermatologists, allergists, immunologists, psychologists, nurse practitioners, physician assistants, and patients “to design a curriculum that provided an entire picture of the patient experience, so that we could go out and educate not only on the basics of eczema and atopic dermatitis for a variety of practitioners ... but also for the specialists who are now going to be engaging in new innovations and new therapies for their patients.”

She was joined by Adam Friedman, MD, professor of dermatology and residency program director at George Washington University, Washington, where the symposium, a resident’s boot camp, was held. The boot camp was somewhat unique in that it was geared more towards trainees; typically, the CUBE-C program is a CME program for practitioners, but this reflects the flexibility of the program, which can be tailored to the audience, Dr. Friedman pointed out. “The hope is that programs like these pop up all over the place ... anywhere you have a critical mass of individuals who want to learn about this,” where planners can choose from a menu of topics provided by CUBE-C – which include therapeutics, infections, pathogenesis, and access to care – and “easily formulate a conference like we held here today for the right audience.”

Topics covered at the George Washington University symposium included the impact of climate on the prevalence of childhood eczema, the diagnosis and differential diagnosis in children, infections in atopic dermatitis patients, and itch treatment.

More information on CUBE-C is available on the NEA website.

The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Friedman reported serving as a speaker for Regeneron, Pfizer, and other companies. He also consults and serves on the advisory board for Pfizer and multiple other companies developing and marketing atopic dermatitis therapies and products.
 

[email protected]

WASHINGTON – The National Eczema Association (NEA) has established the Coalition United for Better Eczema Care (CUBE-C) to provide practitioners with a resource for “trustworthy, up-to-date, state of the art” information on atopic dermatitis, with the goal of improving health outcomes, according to Julie Block, president and chief executive officer of the NEA.

In an interview at a symposium presented by CUBE-C, Ms. Block provided more information on CUBE-C, including how and why it started and what it can offer to dermatologists, as well as primary care physicians, who care for patients with atopic dermatitis. She said that the NEA convened dermatologists, allergists, immunologists, psychologists, nurse practitioners, physician assistants, and patients “to design a curriculum that provided an entire picture of the patient experience, so that we could go out and educate not only on the basics of eczema and atopic dermatitis for a variety of practitioners ... but also for the specialists who are now going to be engaging in new innovations and new therapies for their patients.”

She was joined by Adam Friedman, MD, professor of dermatology and residency program director at George Washington University, Washington, where the symposium, a resident’s boot camp, was held. The boot camp was somewhat unique in that it was geared more towards trainees; typically, the CUBE-C program is a CME program for practitioners, but this reflects the flexibility of the program, which can be tailored to the audience, Dr. Friedman pointed out. “The hope is that programs like these pop up all over the place ... anywhere you have a critical mass of individuals who want to learn about this,” where planners can choose from a menu of topics provided by CUBE-C – which include therapeutics, infections, pathogenesis, and access to care – and “easily formulate a conference like we held here today for the right audience.”

Topics covered at the George Washington University symposium included the impact of climate on the prevalence of childhood eczema, the diagnosis and differential diagnosis in children, infections in atopic dermatitis patients, and itch treatment.

More information on CUBE-C is available on the NEA website.

The symposium was supported by an educational grant from Sanofi Genzyme, Regeneron Pharmaceuticals, and Pfizer. Dr. Friedman reported serving as a speaker for Regeneron, Pfizer, and other companies. He also consults and serves on the advisory board for Pfizer and multiple other companies developing and marketing atopic dermatitis therapies and products.
 

[email protected]

AMSTERDAM – People infected with HIV had a 66% increased rate of developing heart failure – compared with matched, uninfected people – that was independent of any other cardiovascular disease risk factor in a study of roughly 425,000 individuals from a large U.S. health care system.

“HIV infection is independently associated with a higher risk for developing heart failure, and this excess risk does not appear mediated through atherosclerotic disease pathways or differential use of cardioprotective medications,” Alan S. Go, MD, said at the 22nd International AIDS Conference.

The finding sends two important messages to physicians who care for people living with HIV, Dr. Go said in a video interview. First, have “greater awareness for the risk of heart failure” in people living with HIV, even in those who have excellent [HIV] treatment. Be on the lookout, he recommended, for classic symptoms of heart failure like dyspnea and fatigue, and if found follow-up with an assessment of heart function, usually by echocardiography. The second message is to pay attention to and aggressively treat risk factors for heart failure, such as hypertension, smoking, obesity, diabetes, and hypercholesterolemia, said Dr. Go, director of the Comprehensive Clinical Research Unit of Kaiser Permanente in Oakland, Calif.

Results from a small number of prior studies also suggested an increased heart failure rate in people infected with HIV, but those reports had not been able to untangle this observed increase from a possible relationship to the elevated rate of MIs among people living with HIV. The study led by Dr. Go adjusted for acute coronary syndrome events that occurred during follow-up in the analysis and this showed that the increased incidence of heart failure occurred independently of any preceding MI or unstable angina event.

Dr. Go proposed several potential mechanisms that could tie HIV infection to an elevated heart failure risk that was not linked to a prior ischemic heart disease event. The virus could directly damage cardiac myocytes to produce fibrosis, the virus could trigger cardiac inflammation, and the infected person could have an increased susceptibility to infection by a pathogen know to potentially cause cardiac damage and myocarditis such as coxsackievirus.

For the time being, patients infected by HIV who develop heart failure should receive the same treatments that are recommended for the general population, Dr. Go said, but he also highlighted the need for further study to determine the effectiveness of standard heart failure treatments specifically in people living with HIV. He and his associates are also currently analyzing the relationship of several other variables to the risk for heart failure in HIV-infected people, such as the degree of HIV control, and the types of antiretroviral therapy that patients receive. So far the study has not shown a relationship between HIV infection and any specific type of heart failure. About a quarter of the HIV-infected people who developed heart failure in this study had reduced left ventricular ejection fraction, about a quarter had preserved ejection fraction, and for the remaining patients information on their left ventricular ejection fraction was not available, Dr. Go said.

The Kaiser Permanente HIV Heart Study used data from health records from about 13.5 million people enrolled in the health system during 2000-2016 at locations in northern California, southern California, or the mid-Atlantic region. From these records the researchers identified 38,868 people diagnosed with an HIV infection, free of a heart failure diagnosis, and at least 21 years old, and matched them by age, sex, and race with 386,586 people in the health system who were both uninfected and free of heart failure. At “baseline” in the analysis the two study groups had very similar rates of smoking, but those with HIV had somewhat more alcohol abuse and nearly twice the rate of illicit drug use, although even among those with HIV this rate was low at 4%.

Some clinical characteristics at baseline showed significant differences between the two groups. People living with HIV had substantially less hypertension, 7% compared with 12% in those without HIV; half the rate of dyslipidemia, 8% compared with 16% among the control group; and nearly half the prevalence of diabetes, 3% versus 5% among those without HIV. On the other hand, certain other clinical characteristics were more common among those with HIV. The prevalence at baseline of diagnosed dementia was 15% among people infected with HIV and essentially nonexistent (less than 1%) among controls, and the prevalence of diagnosed depression was 8% among people with HIV and 5% among those without the infection.

Baseline parameters also showed that at the time this review first identified a person with HIV and without heart failure in the system records only 18% of the HIV-infected individuals were on an antiretroviral therapy regimen. Dr. Go said that the study is currently analyzing subsequent HIV treatments that these patients may have received. Also at “baseline” 13% of people with documented HIV infection had a CD4 cell count of fewer than 200 cell/mm³, with 4% having fewer than 50 CD4 cells/mm³, and 29% of those with HIV had a blood level of at least 500 copies of HIV RNA/mL. In addition, information on CD4 cell counts was unavailable for 43% of these people, and information on viral load was unavailable for about half.

During “follow-up” in the system’s medical records for a period of up to 17 years, diagnoses of incident heart failure accumulated significantly faster among people with HIV compared to those without HIV. After adjustment for demographic differences, the time of entry into the health system, cardiovascular and other medical differences, and differences in medication use, people living with HIV had a 75% higher rate of incident heart failure compared with those without HIV. Further adjustment based on incident first episodes of acute coronary syndrome during “follow-up” brought the excess rate of heart failure to 66% higher among people infected by HIV, Dr. Go reported. He cautioned that the findings came from a U.S. population that had access to comprehensive health care.

[email protected]

SOURCE: Go AS et al. AIDS 2018, Abstract 2778, THAB0103.

AMSTERDAM – People infected with HIV had a 66% increased rate of developing heart failure – compared with matched, uninfected people – that was independent of any other cardiovascular disease risk factor in a study of roughly 425,000 individuals from a large U.S. health care system.

“HIV infection is independently associated with a higher risk for developing heart failure, and this excess risk does not appear mediated through atherosclerotic disease pathways or differential use of cardioprotective medications,” Alan S. Go, MD, said at the 22nd International AIDS Conference.

The finding sends two important messages to physicians who care for people living with HIV, Dr. Go said in a video interview. First, have “greater awareness for the risk of heart failure” in people living with HIV, even in those who have excellent [HIV] treatment. Be on the lookout, he recommended, for classic symptoms of heart failure like dyspnea and fatigue, and if found follow-up with an assessment of heart function, usually by echocardiography. The second message is to pay attention to and aggressively treat risk factors for heart failure, such as hypertension, smoking, obesity, diabetes, and hypercholesterolemia, said Dr. Go, director of the Comprehensive Clinical Research Unit of Kaiser Permanente in Oakland, Calif.

Results from a small number of prior studies also suggested an increased heart failure rate in people infected with HIV, but those reports had not been able to untangle this observed increase from a possible relationship to the elevated rate of MIs among people living with HIV. The study led by Dr. Go adjusted for acute coronary syndrome events that occurred during follow-up in the analysis and this showed that the increased incidence of heart failure occurred independently of any preceding MI or unstable angina event.

Dr. Go proposed several potential mechanisms that could tie HIV infection to an elevated heart failure risk that was not linked to a prior ischemic heart disease event. The virus could directly damage cardiac myocytes to produce fibrosis, the virus could trigger cardiac inflammation, and the infected person could have an increased susceptibility to infection by a pathogen know to potentially cause cardiac damage and myocarditis such as coxsackievirus.

For the time being, patients infected by HIV who develop heart failure should receive the same treatments that are recommended for the general population, Dr. Go said, but he also highlighted the need for further study to determine the effectiveness of standard heart failure treatments specifically in people living with HIV. He and his associates are also currently analyzing the relationship of several other variables to the risk for heart failure in HIV-infected people, such as the degree of HIV control, and the types of antiretroviral therapy that patients receive. So far the study has not shown a relationship between HIV infection and any specific type of heart failure. About a quarter of the HIV-infected people who developed heart failure in this study had reduced left ventricular ejection fraction, about a quarter had preserved ejection fraction, and for the remaining patients information on their left ventricular ejection fraction was not available, Dr. Go said.

The Kaiser Permanente HIV Heart Study used data from health records from about 13.5 million people enrolled in the health system during 2000-2016 at locations in northern California, southern California, or the mid-Atlantic region. From these records the researchers identified 38,868 people diagnosed with an HIV infection, free of a heart failure diagnosis, and at least 21 years old, and matched them by age, sex, and race with 386,586 people in the health system who were both uninfected and free of heart failure. At “baseline” in the analysis the two study groups had very similar rates of smoking, but those with HIV had somewhat more alcohol abuse and nearly twice the rate of illicit drug use, although even among those with HIV this rate was low at 4%.

Some clinical characteristics at baseline showed significant differences between the two groups. People living with HIV had substantially less hypertension, 7% compared with 12% in those without HIV; half the rate of dyslipidemia, 8% compared with 16% among the control group; and nearly half the prevalence of diabetes, 3% versus 5% among those without HIV. On the other hand, certain other clinical characteristics were more common among those with HIV. The prevalence at baseline of diagnosed dementia was 15% among people infected with HIV and essentially nonexistent (less than 1%) among controls, and the prevalence of diagnosed depression was 8% among people with HIV and 5% among those without the infection.

Baseline parameters also showed that at the time this review first identified a person with HIV and without heart failure in the system records only 18% of the HIV-infected individuals were on an antiretroviral therapy regimen. Dr. Go said that the study is currently analyzing subsequent HIV treatments that these patients may have received. Also at “baseline” 13% of people with documented HIV infection had a CD4 cell count of fewer than 200 cell/mm³, with 4% having fewer than 50 CD4 cells/mm³, and 29% of those with HIV had a blood level of at least 500 copies of HIV RNA/mL. In addition, information on CD4 cell counts was unavailable for 43% of these people, and information on viral load was unavailable for about half.

During “follow-up” in the system’s medical records for a period of up to 17 years, diagnoses of incident heart failure accumulated significantly faster among people with HIV compared to those without HIV. After adjustment for demographic differences, the time of entry into the health system, cardiovascular and other medical differences, and differences in medication use, people living with HIV had a 75% higher rate of incident heart failure compared with those without HIV. Further adjustment based on incident first episodes of acute coronary syndrome during “follow-up” brought the excess rate of heart failure to 66% higher among people infected by HIV, Dr. Go reported. He cautioned that the findings came from a U.S. population that had access to comprehensive health care.

[email protected]

SOURCE: Go AS et al. AIDS 2018, Abstract 2778, THAB0103.

AMSTERDAM – People infected with HIV had a 66% increased rate of developing heart failure – compared with matched, uninfected people – that was independent of any other cardiovascular disease risk factor in a study of roughly 425,000 individuals from a large U.S. health care system.

“HIV infection is independently associated with a higher risk for developing heart failure, and this excess risk does not appear mediated through atherosclerotic disease pathways or differential use of cardioprotective medications,” Alan S. Go, MD, said at the 22nd International AIDS Conference.

The finding sends two important messages to physicians who care for people living with HIV, Dr. Go said in a video interview. First, have “greater awareness for the risk of heart failure” in people living with HIV, even in those who have excellent [HIV] treatment. Be on the lookout, he recommended, for classic symptoms of heart failure like dyspnea and fatigue, and if found follow-up with an assessment of heart function, usually by echocardiography. The second message is to pay attention to and aggressively treat risk factors for heart failure, such as hypertension, smoking, obesity, diabetes, and hypercholesterolemia, said Dr. Go, director of the Comprehensive Clinical Research Unit of Kaiser Permanente in Oakland, Calif.

Results from a small number of prior studies also suggested an increased heart failure rate in people infected with HIV, but those reports had not been able to untangle this observed increase from a possible relationship to the elevated rate of MIs among people living with HIV. The study led by Dr. Go adjusted for acute coronary syndrome events that occurred during follow-up in the analysis and this showed that the increased incidence of heart failure occurred independently of any preceding MI or unstable angina event.

Dr. Go proposed several potential mechanisms that could tie HIV infection to an elevated heart failure risk that was not linked to a prior ischemic heart disease event. The virus could directly damage cardiac myocytes to produce fibrosis, the virus could trigger cardiac inflammation, and the infected person could have an increased susceptibility to infection by a pathogen know to potentially cause cardiac damage and myocarditis such as coxsackievirus.

For the time being, patients infected by HIV who develop heart failure should receive the same treatments that are recommended for the general population, Dr. Go said, but he also highlighted the need for further study to determine the effectiveness of standard heart failure treatments specifically in people living with HIV. He and his associates are also currently analyzing the relationship of several other variables to the risk for heart failure in HIV-infected people, such as the degree of HIV control, and the types of antiretroviral therapy that patients receive. So far the study has not shown a relationship between HIV infection and any specific type of heart failure. About a quarter of the HIV-infected people who developed heart failure in this study had reduced left ventricular ejection fraction, about a quarter had preserved ejection fraction, and for the remaining patients information on their left ventricular ejection fraction was not available, Dr. Go said.

The Kaiser Permanente HIV Heart Study used data from health records from about 13.5 million people enrolled in the health system during 2000-2016 at locations in northern California, southern California, or the mid-Atlantic region. From these records the researchers identified 38,868 people diagnosed with an HIV infection, free of a heart failure diagnosis, and at least 21 years old, and matched them by age, sex, and race with 386,586 people in the health system who were both uninfected and free of heart failure. At “baseline” in the analysis the two study groups had very similar rates of smoking, but those with HIV had somewhat more alcohol abuse and nearly twice the rate of illicit drug use, although even among those with HIV this rate was low at 4%.

Some clinical characteristics at baseline showed significant differences between the two groups. People living with HIV had substantially less hypertension, 7% compared with 12% in those without HIV; half the rate of dyslipidemia, 8% compared with 16% among the control group; and nearly half the prevalence of diabetes, 3% versus 5% among those without HIV. On the other hand, certain other clinical characteristics were more common among those with HIV. The prevalence at baseline of diagnosed dementia was 15% among people infected with HIV and essentially nonexistent (less than 1%) among controls, and the prevalence of diagnosed depression was 8% among people with HIV and 5% among those without the infection.

Baseline parameters also showed that at the time this review first identified a person with HIV and without heart failure in the system records only 18% of the HIV-infected individuals were on an antiretroviral therapy regimen. Dr. Go said that the study is currently analyzing subsequent HIV treatments that these patients may have received. Also at “baseline” 13% of people with documented HIV infection had a CD4 cell count of fewer than 200 cell/mm³, with 4% having fewer than 50 CD4 cells/mm³, and 29% of those with HIV had a blood level of at least 500 copies of HIV RNA/mL. In addition, information on CD4 cell counts was unavailable for 43% of these people, and information on viral load was unavailable for about half.

During “follow-up” in the system’s medical records for a period of up to 17 years, diagnoses of incident heart failure accumulated significantly faster among people with HIV compared to those without HIV. After adjustment for demographic differences, the time of entry into the health system, cardiovascular and other medical differences, and differences in medication use, people living with HIV had a 75% higher rate of incident heart failure compared with those without HIV. Further adjustment based on incident first episodes of acute coronary syndrome during “follow-up” brought the excess rate of heart failure to 66% higher among people infected by HIV, Dr. Go reported. He cautioned that the findings came from a U.S. population that had access to comprehensive health care.

[email protected]

SOURCE: Go AS et al. AIDS 2018, Abstract 2778, THAB0103.

AMSTERDAM – An investigational HIV vaccine that recently began testing in a phase IIb trial showed durable safety and anti-HIV immune responses out to 1 year following the final dosage in the initial phase I/IIa trial that had identified the most effective dosing strategy for the vaccine.

The 96-week follow-up data showed durable humoral and cellular immunity induction by the vaccine and its associated booster, a durable breadth of immune responses to the multiple HIV clades that the vaccine targets, and no serious or grade 3 or 4 adverse effects in the 393 people who participated in the early-phase study, Frank L. Tomaka, MD, said at the 22nd International AIDS Conference.

The 96-week results he reported came from follow-up of the 393 people who received one of several different dosing regimens for an engineered, mosaic HIV vaccine. The vaccine incorporates genes for three different HIV envelope antigens that contain components drawn from several different HIV clades (to induce more broadly protective immunity) into a serotype 26 adenovirus. The immunization regimen also includes treatment with HIV glycoprotein 140 as a booster agent. Dr. Tomaka and his associates reported the primary endpoints from this placebo-controlled study, APPROACH, measured just after the fourth and final immunizing regimen at 48 weeks after the first treatment in a recently published article (Lancet. 2018 Jul 21;392[10143]:232-43).

As part of the study, the investigators administered the vaccine and booster to rhesus monkeys and found that the regimens produced a pattern of immune responses in the monkeys similar to that seen in people. When the monkeys that received the regimen that performed best in people received six monthly challenges with a simian-human immunodeficiency virus that’s related to HIV, the researchers found a 67% efficacy for protection against infection. These “very encouraging” findings led the company developing the vaccine to launch in November 2017 a phase IIb trial, named Imbokodo, in five African countries, with a plan to enroll 2,600 people, Dr. Tomaka said.

“What’s unique and very exciting” about the APPROACH findings are the nonhuman primate findings, and the fact that the vaccine was designed to provide protection against several different HIV clades, Dr. Tomaka said in a video interview. The 67% level of protection against viral challenge in the monkeys is at a level that would be clinically meaningful if replicated in people. A vaccine and booster regimen that provided something in the range of 50%-60% protection or better might be an attractive option in a region with relatively low resources, while in a more developed country a vaccine with a protective efficacy of 70% or better would also likely be seen as an attractive intervention, said Dr. Tomaka, clinical leader for HIV/STI vaccines for Janssen in Titusville, N.J.

[email protected]

SOURCE: Tomaka FL et al. AIDS 2018, Abstract TUAA0104.

AMSTERDAM – An investigational HIV vaccine that recently began testing in a phase IIb trial showed durable safety and anti-HIV immune responses out to 1 year following the final dosage in the initial phase I/IIa trial that had identified the most effective dosing strategy for the vaccine.

The 96-week follow-up data showed durable humoral and cellular immunity induction by the vaccine and its associated booster, a durable breadth of immune responses to the multiple HIV clades that the vaccine targets, and no serious or grade 3 or 4 adverse effects in the 393 people who participated in the early-phase study, Frank L. Tomaka, MD, said at the 22nd International AIDS Conference.

The 96-week results he reported came from follow-up of the 393 people who received one of several different dosing regimens for an engineered, mosaic HIV vaccine. The vaccine incorporates genes for three different HIV envelope antigens that contain components drawn from several different HIV clades (to induce more broadly protective immunity) into a serotype 26 adenovirus. The immunization regimen also includes treatment with HIV glycoprotein 140 as a booster agent. Dr. Tomaka and his associates reported the primary endpoints from this placebo-controlled study, APPROACH, measured just after the fourth and final immunizing regimen at 48 weeks after the first treatment in a recently published article (Lancet. 2018 Jul 21;392[10143]:232-43).

As part of the study, the investigators administered the vaccine and booster to rhesus monkeys and found that the regimens produced a pattern of immune responses in the monkeys similar to that seen in people. When the monkeys that received the regimen that performed best in people received six monthly challenges with a simian-human immunodeficiency virus that’s related to HIV, the researchers found a 67% efficacy for protection against infection. These “very encouraging” findings led the company developing the vaccine to launch in November 2017 a phase IIb trial, named Imbokodo, in five African countries, with a plan to enroll 2,600 people, Dr. Tomaka said.

“What’s unique and very exciting” about the APPROACH findings are the nonhuman primate findings, and the fact that the vaccine was designed to provide protection against several different HIV clades, Dr. Tomaka said in a video interview. The 67% level of protection against viral challenge in the monkeys is at a level that would be clinically meaningful if replicated in people. A vaccine and booster regimen that provided something in the range of 50%-60% protection or better might be an attractive option in a region with relatively low resources, while in a more developed country a vaccine with a protective efficacy of 70% or better would also likely be seen as an attractive intervention, said Dr. Tomaka, clinical leader for HIV/STI vaccines for Janssen in Titusville, N.J.

[email protected]

SOURCE: Tomaka FL et al. AIDS 2018, Abstract TUAA0104.

AMSTERDAM – An investigational HIV vaccine that recently began testing in a phase IIb trial showed durable safety and anti-HIV immune responses out to 1 year following the final dosage in the initial phase I/IIa trial that had identified the most effective dosing strategy for the vaccine.

The 96-week follow-up data showed durable humoral and cellular immunity induction by the vaccine and its associated booster, a durable breadth of immune responses to the multiple HIV clades that the vaccine targets, and no serious or grade 3 or 4 adverse effects in the 393 people who participated in the early-phase study, Frank L. Tomaka, MD, said at the 22nd International AIDS Conference.

The 96-week results he reported came from follow-up of the 393 people who received one of several different dosing regimens for an engineered, mosaic HIV vaccine. The vaccine incorporates genes for three different HIV envelope antigens that contain components drawn from several different HIV clades (to induce more broadly protective immunity) into a serotype 26 adenovirus. The immunization regimen also includes treatment with HIV glycoprotein 140 as a booster agent. Dr. Tomaka and his associates reported the primary endpoints from this placebo-controlled study, APPROACH, measured just after the fourth and final immunizing regimen at 48 weeks after the first treatment in a recently published article (Lancet. 2018 Jul 21;392[10143]:232-43).

As part of the study, the investigators administered the vaccine and booster to rhesus monkeys and found that the regimens produced a pattern of immune responses in the monkeys similar to that seen in people. When the monkeys that received the regimen that performed best in people received six monthly challenges with a simian-human immunodeficiency virus that’s related to HIV, the researchers found a 67% efficacy for protection against infection. These “very encouraging” findings led the company developing the vaccine to launch in November 2017 a phase IIb trial, named Imbokodo, in five African countries, with a plan to enroll 2,600 people, Dr. Tomaka said.

“What’s unique and very exciting” about the APPROACH findings are the nonhuman primate findings, and the fact that the vaccine was designed to provide protection against several different HIV clades, Dr. Tomaka said in a video interview. The 67% level of protection against viral challenge in the monkeys is at a level that would be clinically meaningful if replicated in people. A vaccine and booster regimen that provided something in the range of 50%-60% protection or better might be an attractive option in a region with relatively low resources, while in a more developed country a vaccine with a protective efficacy of 70% or better would also likely be seen as an attractive intervention, said Dr. Tomaka, clinical leader for HIV/STI vaccines for Janssen in Titusville, N.J.

[email protected]

SOURCE: Tomaka FL et al. AIDS 2018, Abstract TUAA0104.

ORLANDO – Research suggests that HIV-positive people who take the latest generations of AIDS medications are living almost as long as everyone else. But they still face special medical challenges, and an endocrinologist urged colleagues to adjust their approaches to diabetes in these patients.

“The HIV population is indeed aging, diabetes is very common, and there are some unique pathophysiologic and management considerations,” said Todd T. Brown, MD, PhD, of Johns Hopkins Medicine, Baltimore, in a presentation at the annual scientific sessions of the American Diabetes Association.

It’s not just a matter of subbing in an alternate drug here or there. When it comes to diabetes, patients with HIV require significant adjustments to diagnosis and treatment, Dr. Brown said.

In terms of diagnosis, treatment guidelines approved by the Infectious Diseases Society of America and ADA recommend that all HIV-positive patients be tested for diabetes before they begin taking antiretroviral therapy. Then, the guidelines suggest, they should be tested 4-6 weeks after initiation of therapy, and every 6-12 months going forward.

“It’s a bit of overkill to go every 6 months,” said Dr. Brown, who prefers an annual testing approach. He added that research has suggested that the 2-hour postload glucose test is more sensitive than the fasting glucose test in some HIV-positive populations. However, he believes that it’s generally fine to give a fasting glucose test before initiation of therapy – and on an annual basis afterward – rather than the more cumbersome postload test.

Still, he said, the postload test may be appropriate in a patient with impaired glucose tolerance “if you really want to make the diagnosis, and especially if you’ll change your treatment based on it.”

Ongoing treatment of HIV-positive patients also presents unique challenges, he said. For one, antiretroviral therapy seems to affect glucose metabolism and body fat, he said, and findings from a 2016 study suggest HIV-positive people who begin antiretroviral therapy face a higher risk of developing diabetes after weight gain (J Acquir Immune Defic Syndr. 2016 Oct 1;73[2]:228-36).

One option is to switch patients to integrase inhibitors, but findings from a 2017 study suggested that this may also lead to more weight gain, Dr. Brown said.

“This has been an evolving story,” he said. “The clinical consequences of this are unclear. This is a topic that’s being hotly investigated now in the HIV health world” (JAIDS. 2017 Dec 15;76[5]:527-31).

As for other diabetes management issues, Dr. Brown noted that hemoglobin A_1c tests appear to underestimate glycemia in HIV-infected patients. He suggested that goal HbA_1c levels should be lower in diabetic patients with HIV, especially those with CD4+ counts under 500 cells /mm³ and/or mean cell volume over 100 fL.

Research suggests that lifestyle changes seem to work well in HIV-positive patients, he said, and metformin is the ideal first-line drug treatment just as in the HIV-negative population. “It’s a good drug. We all love it,” he said. “It may improve lipohypertrophy and coronary plaque.”

He added that proteinuria and neuropathy are more common in HIV-positive patients with diabetes. He said levels of neuropathy and nephropathy could be related to AIDS drugs.

On the medication front, Dr. Brown cautioned about certain drugs in HIV-positive patients: The HIV drug dolutegravir increases metformin concentrations by about 80%, he said, and there are concerns about bone and cardiac health in HIV-positive patients who take the diabetes medications known as thiazolidinediones (glitazones).

He added that there are sparse data about the use of several types of diabetes drugs – DPP IV inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors – in HIV-positive patients.

Dr. Brown discloses consulting for Gilead Sciences, ViiV, BMS, Merck, Theratechnologies, and EMD Serono.

ORLANDO – Research suggests that HIV-positive people who take the latest generations of AIDS medications are living almost as long as everyone else. But they still face special medical challenges, and an endocrinologist urged colleagues to adjust their approaches to diabetes in these patients.

“The HIV population is indeed aging, diabetes is very common, and there are some unique pathophysiologic and management considerations,” said Todd T. Brown, MD, PhD, of Johns Hopkins Medicine, Baltimore, in a presentation at the annual scientific sessions of the American Diabetes Association.

It’s not just a matter of subbing in an alternate drug here or there. When it comes to diabetes, patients with HIV require significant adjustments to diagnosis and treatment, Dr. Brown said.

In terms of diagnosis, treatment guidelines approved by the Infectious Diseases Society of America and ADA recommend that all HIV-positive patients be tested for diabetes before they begin taking antiretroviral therapy. Then, the guidelines suggest, they should be tested 4-6 weeks after initiation of therapy, and every 6-12 months going forward.

“It’s a bit of overkill to go every 6 months,” said Dr. Brown, who prefers an annual testing approach. He added that research has suggested that the 2-hour postload glucose test is more sensitive than the fasting glucose test in some HIV-positive populations. However, he believes that it’s generally fine to give a fasting glucose test before initiation of therapy – and on an annual basis afterward – rather than the more cumbersome postload test.

Still, he said, the postload test may be appropriate in a patient with impaired glucose tolerance “if you really want to make the diagnosis, and especially if you’ll change your treatment based on it.”

Ongoing treatment of HIV-positive patients also presents unique challenges, he said. For one, antiretroviral therapy seems to affect glucose metabolism and body fat, he said, and findings from a 2016 study suggest HIV-positive people who begin antiretroviral therapy face a higher risk of developing diabetes after weight gain (J Acquir Immune Defic Syndr. 2016 Oct 1;73[2]:228-36).

One option is to switch patients to integrase inhibitors, but findings from a 2017 study suggested that this may also lead to more weight gain, Dr. Brown said.

“This has been an evolving story,” he said. “The clinical consequences of this are unclear. This is a topic that’s being hotly investigated now in the HIV health world” (JAIDS. 2017 Dec 15;76[5]:527-31).

As for other diabetes management issues, Dr. Brown noted that hemoglobin A_1c tests appear to underestimate glycemia in HIV-infected patients. He suggested that goal HbA_1c levels should be lower in diabetic patients with HIV, especially those with CD4+ counts under 500 cells /mm³ and/or mean cell volume over 100 fL.

Research suggests that lifestyle changes seem to work well in HIV-positive patients, he said, and metformin is the ideal first-line drug treatment just as in the HIV-negative population. “It’s a good drug. We all love it,” he said. “It may improve lipohypertrophy and coronary plaque.”

He added that proteinuria and neuropathy are more common in HIV-positive patients with diabetes. He said levels of neuropathy and nephropathy could be related to AIDS drugs.

On the medication front, Dr. Brown cautioned about certain drugs in HIV-positive patients: The HIV drug dolutegravir increases metformin concentrations by about 80%, he said, and there are concerns about bone and cardiac health in HIV-positive patients who take the diabetes medications known as thiazolidinediones (glitazones).

He added that there are sparse data about the use of several types of diabetes drugs – DPP IV inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors – in HIV-positive patients.

Dr. Brown discloses consulting for Gilead Sciences, ViiV, BMS, Merck, Theratechnologies, and EMD Serono.

ORLANDO – Research suggests that HIV-positive people who take the latest generations of AIDS medications are living almost as long as everyone else. But they still face special medical challenges, and an endocrinologist urged colleagues to adjust their approaches to diabetes in these patients.

“The HIV population is indeed aging, diabetes is very common, and there are some unique pathophysiologic and management considerations,” said Todd T. Brown, MD, PhD, of Johns Hopkins Medicine, Baltimore, in a presentation at the annual scientific sessions of the American Diabetes Association.

It’s not just a matter of subbing in an alternate drug here or there. When it comes to diabetes, patients with HIV require significant adjustments to diagnosis and treatment, Dr. Brown said.

In terms of diagnosis, treatment guidelines approved by the Infectious Diseases Society of America and ADA recommend that all HIV-positive patients be tested for diabetes before they begin taking antiretroviral therapy. Then, the guidelines suggest, they should be tested 4-6 weeks after initiation of therapy, and every 6-12 months going forward.

“It’s a bit of overkill to go every 6 months,” said Dr. Brown, who prefers an annual testing approach. He added that research has suggested that the 2-hour postload glucose test is more sensitive than the fasting glucose test in some HIV-positive populations. However, he believes that it’s generally fine to give a fasting glucose test before initiation of therapy – and on an annual basis afterward – rather than the more cumbersome postload test.

Still, he said, the postload test may be appropriate in a patient with impaired glucose tolerance “if you really want to make the diagnosis, and especially if you’ll change your treatment based on it.”

Ongoing treatment of HIV-positive patients also presents unique challenges, he said. For one, antiretroviral therapy seems to affect glucose metabolism and body fat, he said, and findings from a 2016 study suggest HIV-positive people who begin antiretroviral therapy face a higher risk of developing diabetes after weight gain (J Acquir Immune Defic Syndr. 2016 Oct 1;73[2]:228-36).

One option is to switch patients to integrase inhibitors, but findings from a 2017 study suggested that this may also lead to more weight gain, Dr. Brown said.

“This has been an evolving story,” he said. “The clinical consequences of this are unclear. This is a topic that’s being hotly investigated now in the HIV health world” (JAIDS. 2017 Dec 15;76[5]:527-31).

As for other diabetes management issues, Dr. Brown noted that hemoglobin A_1c tests appear to underestimate glycemia in HIV-infected patients. He suggested that goal HbA_1c levels should be lower in diabetic patients with HIV, especially those with CD4+ counts under 500 cells /mm³ and/or mean cell volume over 100 fL.

Research suggests that lifestyle changes seem to work well in HIV-positive patients, he said, and metformin is the ideal first-line drug treatment just as in the HIV-negative population. “It’s a good drug. We all love it,” he said. “It may improve lipohypertrophy and coronary plaque.”

He added that proteinuria and neuropathy are more common in HIV-positive patients with diabetes. He said levels of neuropathy and nephropathy could be related to AIDS drugs.

On the medication front, Dr. Brown cautioned about certain drugs in HIV-positive patients: The HIV drug dolutegravir increases metformin concentrations by about 80%, he said, and there are concerns about bone and cardiac health in HIV-positive patients who take the diabetes medications known as thiazolidinediones (glitazones).

He added that there are sparse data about the use of several types of diabetes drugs – DPP IV inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors – in HIV-positive patients.

Dr. Brown discloses consulting for Gilead Sciences, ViiV, BMS, Merck, Theratechnologies, and EMD Serono.