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Neural-tube defect signal from dolutegravir HIV treatment raises concerns
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.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
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.
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.
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.
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.
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.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
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.
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.
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.
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.
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.
“Dolutegravir has been a beacon of hope for treating HIV,” said Maggie Little, PhD, a professor of philosophy and medical ethicist at Georgetown University in Washington. “Dolutegravir offers substantial benefits to quality of life in addition to reducing women’s mortality.” The new finding of excess NTDs “appears to pit pregnant women against their children. But the numbers never tell us the answer; it’s not arithmetic.” The appropriate public health response should focus on “supporting meaningful choice by women,” Dr. Little said during a talk at the session. “Policies must be made in ongoing consultation with communities of women who live with HIV.”
Rise of the INSTIs
The International AIDS Conference showcased the contrast between the benefits of the INSTIs and their possible perils.
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.
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.
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.
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.
REPORTING FROM AIDS 2018
U.S. HIV clinical care fails the hardest hit
AMSTERDAM – The U.S. HIV epidemic during this decade has shown an overall slow but steady decline, with national incidence rates dropping by 5% during 2011-2016. But preventing new HIV infections is clearly falling short for a few, key demographic slices that make up the vast majority of the roughly 40,000 new U.S. HIV cases annually in recent years: black/African American men, Hispanic/Latino men, men who have sex with men (MSM), and young adults aged 25-34 years.
What’s especially glaring in data from the Centers for Disease Control and Prevention are the increasing incidence rates when these groups overlap, compared with falling rates of new HIV infections for most everyone else. The CDC’s numbers for 2010-2015 show statistically significant increases in HIV incidence among MSM aged 25-34 years who are black/African American or Hispanic/Latino. Black/African American MSM accounted for 26% of the total 39,782 U.S. HIV diagnoses in 2016, and Hispanic/Latino MSM accounted for 19%, according to CDC statistics, while all blacks/African Americans accounted for 44% of 2016’s new HIV infections and all Hispanic/Latinos had 25%.
Why are these relatively small demographic subgroups bucking the overall national trend toward fewer infections? Why are their incidence rates so stubbornly high?
A major reason is that the U.S. medical community that delivers HIV prevention, diagnosis, and treatment has fallen short in reaching out to, engaging, and facilitating HIV services to these hardest-hit groups, David Malebranche, MD, said in a plenary talk at the 22nd International AIDS Conference. He cited several factors that contribute to the HIV high-risk populations from getting the care they need.
First, there is HIV stigma, which can be especially acute when accompanied by stigmatization that’s also based on race, ethnicity, and sexual orientation.
“HIV stigma causes difficulties in navigating the HIV treatment cascade. HIV stigma can adversely affect testing behavior, disclosure to sex partners and loved ones, and medical care access,” said Dr. Malebranche, an internal medicine physician and HIV specialist at Morehouse School of Medicine in Atlanta who described himself during his talk as a “ black, same-gender-loving man.” People diagnosed with HIV “will consciously choose to live in a trancelike denial of HIV,” he noted. He also cited criminalization of HIV status as another driver of stigmatization, with 34 states having HIV-specific criminal laws, sentence enhancements, or both.
Beyond HIV status, other stigmas permeate clinics based on race, sex, sexual orientation, immigrant status, and gender identity. A need exists to “study what patients experience in clinics, to identify the barriers to patient engagement and antiretroviral therapy,” but Dr. Malebranche suggested that the HIV medical community is “afraid to evaluate and assess their systems because they’re scared of what they’ll see.” U.S. HIV care has been too focused on scientific advances while “losing sight of the larger social picture,” he maintained.
“The power differential between medical systems and vulnerable communities may be partly responsible for why viral suppressions rates are so low.”
Dr. Malebranche placed much of the blame on the HIV clinical community for failing to engage patients in the most affected demographic groups.
“If a health system or clinic has problems with patient adherence, it needs to self-examine the service it provides. Most research into black MSM and the HIV treatment cascade has looked at what’s wrong in the community first and has only looked at the medical community much later, if at all,” Dr. Malebranche said. “Medical systems say things like ‘they are hard to reach,’ and ‘they don’t trust doctors,’ and ‘they are uneducated.’ Medical systems do this to avoid holding themselves accountable.”
But the people who run these systems often don’t question whether the paperwork is too onerous, certification to receive care is too cumbersome, the location too stigmatizing, and whether the staff is trained in cultural humility. “Blaming the victim doesn’t get us far in public health,” he said. The people who run and staff U.S. HIV programs “should consider the power dynamics created by some of their spaces, employees, and protocols that make them complicit in perpetuating vulnerability, and this may be why patients fall out of care. Don’t call black and same-gender-loving people ‘hard to reach’ just because you don’t know how to reach them,” he said.
In addition to calling for better appreciation of the target populations and better accommodation of their needs, Dr. Malebranche suggested greater use of peer navigators, case managers, social workers, rapid test and treat programs, and attention to overall patient health and not just their HIV status. Fundamentally, he said, the HIV medical community needs to go beyond thinking in terms of just HIV suppression and “practice the art of medicine to keep patients engaged.”
SOURCE: Malebranche D, AIDS 2018, Abstract THPL0107.
AMSTERDAM – The U.S. HIV epidemic during this decade has shown an overall slow but steady decline, with national incidence rates dropping by 5% during 2011-2016. But preventing new HIV infections is clearly falling short for a few, key demographic slices that make up the vast majority of the roughly 40,000 new U.S. HIV cases annually in recent years: black/African American men, Hispanic/Latino men, men who have sex with men (MSM), and young adults aged 25-34 years.
What’s especially glaring in data from the Centers for Disease Control and Prevention are the increasing incidence rates when these groups overlap, compared with falling rates of new HIV infections for most everyone else. The CDC’s numbers for 2010-2015 show statistically significant increases in HIV incidence among MSM aged 25-34 years who are black/African American or Hispanic/Latino. Black/African American MSM accounted for 26% of the total 39,782 U.S. HIV diagnoses in 2016, and Hispanic/Latino MSM accounted for 19%, according to CDC statistics, while all blacks/African Americans accounted for 44% of 2016’s new HIV infections and all Hispanic/Latinos had 25%.
Why are these relatively small demographic subgroups bucking the overall national trend toward fewer infections? Why are their incidence rates so stubbornly high?
A major reason is that the U.S. medical community that delivers HIV prevention, diagnosis, and treatment has fallen short in reaching out to, engaging, and facilitating HIV services to these hardest-hit groups, David Malebranche, MD, said in a plenary talk at the 22nd International AIDS Conference. He cited several factors that contribute to the HIV high-risk populations from getting the care they need.
First, there is HIV stigma, which can be especially acute when accompanied by stigmatization that’s also based on race, ethnicity, and sexual orientation.
“HIV stigma causes difficulties in navigating the HIV treatment cascade. HIV stigma can adversely affect testing behavior, disclosure to sex partners and loved ones, and medical care access,” said Dr. Malebranche, an internal medicine physician and HIV specialist at Morehouse School of Medicine in Atlanta who described himself during his talk as a “ black, same-gender-loving man.” People diagnosed with HIV “will consciously choose to live in a trancelike denial of HIV,” he noted. He also cited criminalization of HIV status as another driver of stigmatization, with 34 states having HIV-specific criminal laws, sentence enhancements, or both.
Beyond HIV status, other stigmas permeate clinics based on race, sex, sexual orientation, immigrant status, and gender identity. A need exists to “study what patients experience in clinics, to identify the barriers to patient engagement and antiretroviral therapy,” but Dr. Malebranche suggested that the HIV medical community is “afraid to evaluate and assess their systems because they’re scared of what they’ll see.” U.S. HIV care has been too focused on scientific advances while “losing sight of the larger social picture,” he maintained.
“The power differential between medical systems and vulnerable communities may be partly responsible for why viral suppressions rates are so low.”
Dr. Malebranche placed much of the blame on the HIV clinical community for failing to engage patients in the most affected demographic groups.
“If a health system or clinic has problems with patient adherence, it needs to self-examine the service it provides. Most research into black MSM and the HIV treatment cascade has looked at what’s wrong in the community first and has only looked at the medical community much later, if at all,” Dr. Malebranche said. “Medical systems say things like ‘they are hard to reach,’ and ‘they don’t trust doctors,’ and ‘they are uneducated.’ Medical systems do this to avoid holding themselves accountable.”
But the people who run these systems often don’t question whether the paperwork is too onerous, certification to receive care is too cumbersome, the location too stigmatizing, and whether the staff is trained in cultural humility. “Blaming the victim doesn’t get us far in public health,” he said. The people who run and staff U.S. HIV programs “should consider the power dynamics created by some of their spaces, employees, and protocols that make them complicit in perpetuating vulnerability, and this may be why patients fall out of care. Don’t call black and same-gender-loving people ‘hard to reach’ just because you don’t know how to reach them,” he said.
In addition to calling for better appreciation of the target populations and better accommodation of their needs, Dr. Malebranche suggested greater use of peer navigators, case managers, social workers, rapid test and treat programs, and attention to overall patient health and not just their HIV status. Fundamentally, he said, the HIV medical community needs to go beyond thinking in terms of just HIV suppression and “practice the art of medicine to keep patients engaged.”
SOURCE: Malebranche D, AIDS 2018, Abstract THPL0107.
AMSTERDAM – The U.S. HIV epidemic during this decade has shown an overall slow but steady decline, with national incidence rates dropping by 5% during 2011-2016. But preventing new HIV infections is clearly falling short for a few, key demographic slices that make up the vast majority of the roughly 40,000 new U.S. HIV cases annually in recent years: black/African American men, Hispanic/Latino men, men who have sex with men (MSM), and young adults aged 25-34 years.
What’s especially glaring in data from the Centers for Disease Control and Prevention are the increasing incidence rates when these groups overlap, compared with falling rates of new HIV infections for most everyone else. The CDC’s numbers for 2010-2015 show statistically significant increases in HIV incidence among MSM aged 25-34 years who are black/African American or Hispanic/Latino. Black/African American MSM accounted for 26% of the total 39,782 U.S. HIV diagnoses in 2016, and Hispanic/Latino MSM accounted for 19%, according to CDC statistics, while all blacks/African Americans accounted for 44% of 2016’s new HIV infections and all Hispanic/Latinos had 25%.
Why are these relatively small demographic subgroups bucking the overall national trend toward fewer infections? Why are their incidence rates so stubbornly high?
A major reason is that the U.S. medical community that delivers HIV prevention, diagnosis, and treatment has fallen short in reaching out to, engaging, and facilitating HIV services to these hardest-hit groups, David Malebranche, MD, said in a plenary talk at the 22nd International AIDS Conference. He cited several factors that contribute to the HIV high-risk populations from getting the care they need.
First, there is HIV stigma, which can be especially acute when accompanied by stigmatization that’s also based on race, ethnicity, and sexual orientation.
“HIV stigma causes difficulties in navigating the HIV treatment cascade. HIV stigma can adversely affect testing behavior, disclosure to sex partners and loved ones, and medical care access,” said Dr. Malebranche, an internal medicine physician and HIV specialist at Morehouse School of Medicine in Atlanta who described himself during his talk as a “ black, same-gender-loving man.” People diagnosed with HIV “will consciously choose to live in a trancelike denial of HIV,” he noted. He also cited criminalization of HIV status as another driver of stigmatization, with 34 states having HIV-specific criminal laws, sentence enhancements, or both.
Beyond HIV status, other stigmas permeate clinics based on race, sex, sexual orientation, immigrant status, and gender identity. A need exists to “study what patients experience in clinics, to identify the barriers to patient engagement and antiretroviral therapy,” but Dr. Malebranche suggested that the HIV medical community is “afraid to evaluate and assess their systems because they’re scared of what they’ll see.” U.S. HIV care has been too focused on scientific advances while “losing sight of the larger social picture,” he maintained.
“The power differential between medical systems and vulnerable communities may be partly responsible for why viral suppressions rates are so low.”
Dr. Malebranche placed much of the blame on the HIV clinical community for failing to engage patients in the most affected demographic groups.
“If a health system or clinic has problems with patient adherence, it needs to self-examine the service it provides. Most research into black MSM and the HIV treatment cascade has looked at what’s wrong in the community first and has only looked at the medical community much later, if at all,” Dr. Malebranche said. “Medical systems say things like ‘they are hard to reach,’ and ‘they don’t trust doctors,’ and ‘they are uneducated.’ Medical systems do this to avoid holding themselves accountable.”
But the people who run these systems often don’t question whether the paperwork is too onerous, certification to receive care is too cumbersome, the location too stigmatizing, and whether the staff is trained in cultural humility. “Blaming the victim doesn’t get us far in public health,” he said. The people who run and staff U.S. HIV programs “should consider the power dynamics created by some of their spaces, employees, and protocols that make them complicit in perpetuating vulnerability, and this may be why patients fall out of care. Don’t call black and same-gender-loving people ‘hard to reach’ just because you don’t know how to reach them,” he said.
In addition to calling for better appreciation of the target populations and better accommodation of their needs, Dr. Malebranche suggested greater use of peer navigators, case managers, social workers, rapid test and treat programs, and attention to overall patient health and not just their HIV status. Fundamentally, he said, the HIV medical community needs to go beyond thinking in terms of just HIV suppression and “practice the art of medicine to keep patients engaged.”
SOURCE: Malebranche D, AIDS 2018, Abstract THPL0107.
REPORTING FROM AIDS 2018
Dolutegravir plus 3TC matches three drugs for HIV control
AMSTERDAM – A two-drug antiretroviral regimen with an integrase inhibitor was noninferior to a standard three-drug regimen for controlling HIV viral load in a pair of identical, phase 3, multicenter, randomized trials with more than 1,400 patients.
The efficacy and safety results seen in the two studies at the primary endpoint follow-up of 48 weeks support the tested combination of the integrase inhibitor dolutegravir (Tivicay) plus the nucleoside reverse transcriptase inhibitor (RTI) lamivudine (3TC, Epivir) as an “effective option,” Pedro Cahn, MD, said at the 22nd International AIDS Conference.
The two trials from which he reported results, GEMINI-1 and GEMINI-2, which both compared the dolutegravir (DTG) plus 3TC regimen against DTG plus the nucleotide RTI tenofovir (Viread) and the nucleoside RTI emtricitabine (Emtriva), together showed after 48 weeks on treatment a 91% rate of complete virologic response to DTG plus 3TC with fewer than 50 detectable HIV RNA copies per mL, compared with a 93% complete response among patients on DTG plus tenofovir and emtricitabine. The efficacy of the two-drug regimen fell within the prespecified definition of noninferiority, compared with the three-drug comparator arm, the primary endpoint for both studies, said Dr. Cahn, scientific director of Fundacion Huesped in Buenos Aires, and professor of infectious diseases at Buenos Aires University.
“This is the first time a randomized, controlled trial showed the noninferiority of a two-drug regimen, compared with a three-drug regimen while using an integrase inhibitor as the core drug,” Dr. Cahn said. The goal of cutting the treatment regimen down to two drugs is to “reduce drug burden” and potentially produce fewer adverse effects and reduce cost, he explained.
Integrase strand transport inhibitors like DTG make sense as the core drug because “as a class they quickly reduce viral load” and have several other very attractive properties including good tolerability, a high barrier to resistance mutations, quick recovery of CD4 cell levels, and good adherence by patients, said Dr. Cahn. These advantages apply not only to DTG but also to other drugs in the class: raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Biktarvy). Integrase inhibitors have been specified as part of the preferred anti-HIV regimen for most people starting HIV treatment by public health officials in several countries as well as by the World Health Organization in its 2018 revised HIV treatment recommendations.
But Dr. Cahn put a few qualifications on the findings so far for the combination of DTG and 3TC. Its durability has been tested out only to 48 weeks, although during that time no resistant HIV was seen. The studies will continue to follow the patients on dual treatment for as long as 144 weeks, he said. Also, the two-drug regimen should be considered, for the time being, only for patients who match the enrollment criteria for the GEMINI trials: Patients with a viral load no greater than 500,000 RNA copies/mL, no prior treatment, no evidence of preexisting viral resistance to any anti-HIV drugs, and no hepatitis B virus infection or need for hepatitis C virus treatment. Also there is uncertainty about the risk that women who become pregnant while on DTG have for giving birth to an infant with a neural tube defect. A recent report documented preliminary evidence for an increased risk (N Engl J Med. 2018 Jul 24. doi: 10.1056/NEJMc180765).
In addition to its noninferior efficacy, compared with a triple-drug regimen, the dual regimen showed good safety and tolerance, with a 7% incidence of serious adverse events and a 2% rate of events leading to withdrawal of treatment, rates similar to the triple-drug arm. The dual regimen also showed less evidence for renal damage than the triple regimen, including a statistically significant smaller drop in glomerular filtration rate than the triple regimen and no spikes in urine markers of renal damage as occurred on three drugs. Two drugs also induced no increases in markers of bone metabolism, but this happened with three drugs, Dr. Cahn reported.
The combined data from the two GEMINI studies enrolled 1,433 HIV-infected patients at centers in 21 countries including several U.S. centers. Patients averaged about 33 years old, 85% were men, and more than 90% had a CD4 cell count greater than 200 cell/mL at enrollment. Eighty percent had a viral load of no more than 100,00 RNA copies/mL, and the 20% with higher viral loads were stratified in equal numbers into the two treatment arms.
The 91% and 93% virologic response rates in the two treatment arms came in the intention-to-treat analysis and correlated with similar average rises among patients in the two arms in CD4 cell counts after 48 weeks of 224-228 cell/mm3. In the per protocol analysis the virologic response rates were 93% with the dual regimen and 94% with the triple regimen
SOURCE: Cahn P et al. AIDS 2018, Abstract 13210.
AMSTERDAM – A two-drug antiretroviral regimen with an integrase inhibitor was noninferior to a standard three-drug regimen for controlling HIV viral load in a pair of identical, phase 3, multicenter, randomized trials with more than 1,400 patients.
The efficacy and safety results seen in the two studies at the primary endpoint follow-up of 48 weeks support the tested combination of the integrase inhibitor dolutegravir (Tivicay) plus the nucleoside reverse transcriptase inhibitor (RTI) lamivudine (3TC, Epivir) as an “effective option,” Pedro Cahn, MD, said at the 22nd International AIDS Conference.
The two trials from which he reported results, GEMINI-1 and GEMINI-2, which both compared the dolutegravir (DTG) plus 3TC regimen against DTG plus the nucleotide RTI tenofovir (Viread) and the nucleoside RTI emtricitabine (Emtriva), together showed after 48 weeks on treatment a 91% rate of complete virologic response to DTG plus 3TC with fewer than 50 detectable HIV RNA copies per mL, compared with a 93% complete response among patients on DTG plus tenofovir and emtricitabine. The efficacy of the two-drug regimen fell within the prespecified definition of noninferiority, compared with the three-drug comparator arm, the primary endpoint for both studies, said Dr. Cahn, scientific director of Fundacion Huesped in Buenos Aires, and professor of infectious diseases at Buenos Aires University.
“This is the first time a randomized, controlled trial showed the noninferiority of a two-drug regimen, compared with a three-drug regimen while using an integrase inhibitor as the core drug,” Dr. Cahn said. The goal of cutting the treatment regimen down to two drugs is to “reduce drug burden” and potentially produce fewer adverse effects and reduce cost, he explained.
Integrase strand transport inhibitors like DTG make sense as the core drug because “as a class they quickly reduce viral load” and have several other very attractive properties including good tolerability, a high barrier to resistance mutations, quick recovery of CD4 cell levels, and good adherence by patients, said Dr. Cahn. These advantages apply not only to DTG but also to other drugs in the class: raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Biktarvy). Integrase inhibitors have been specified as part of the preferred anti-HIV regimen for most people starting HIV treatment by public health officials in several countries as well as by the World Health Organization in its 2018 revised HIV treatment recommendations.
But Dr. Cahn put a few qualifications on the findings so far for the combination of DTG and 3TC. Its durability has been tested out only to 48 weeks, although during that time no resistant HIV was seen. The studies will continue to follow the patients on dual treatment for as long as 144 weeks, he said. Also, the two-drug regimen should be considered, for the time being, only for patients who match the enrollment criteria for the GEMINI trials: Patients with a viral load no greater than 500,000 RNA copies/mL, no prior treatment, no evidence of preexisting viral resistance to any anti-HIV drugs, and no hepatitis B virus infection or need for hepatitis C virus treatment. Also there is uncertainty about the risk that women who become pregnant while on DTG have for giving birth to an infant with a neural tube defect. A recent report documented preliminary evidence for an increased risk (N Engl J Med. 2018 Jul 24. doi: 10.1056/NEJMc180765).
In addition to its noninferior efficacy, compared with a triple-drug regimen, the dual regimen showed good safety and tolerance, with a 7% incidence of serious adverse events and a 2% rate of events leading to withdrawal of treatment, rates similar to the triple-drug arm. The dual regimen also showed less evidence for renal damage than the triple regimen, including a statistically significant smaller drop in glomerular filtration rate than the triple regimen and no spikes in urine markers of renal damage as occurred on three drugs. Two drugs also induced no increases in markers of bone metabolism, but this happened with three drugs, Dr. Cahn reported.
The combined data from the two GEMINI studies enrolled 1,433 HIV-infected patients at centers in 21 countries including several U.S. centers. Patients averaged about 33 years old, 85% were men, and more than 90% had a CD4 cell count greater than 200 cell/mL at enrollment. Eighty percent had a viral load of no more than 100,00 RNA copies/mL, and the 20% with higher viral loads were stratified in equal numbers into the two treatment arms.
The 91% and 93% virologic response rates in the two treatment arms came in the intention-to-treat analysis and correlated with similar average rises among patients in the two arms in CD4 cell counts after 48 weeks of 224-228 cell/mm3. In the per protocol analysis the virologic response rates were 93% with the dual regimen and 94% with the triple regimen
SOURCE: Cahn P et al. AIDS 2018, Abstract 13210.
AMSTERDAM – A two-drug antiretroviral regimen with an integrase inhibitor was noninferior to a standard three-drug regimen for controlling HIV viral load in a pair of identical, phase 3, multicenter, randomized trials with more than 1,400 patients.
The efficacy and safety results seen in the two studies at the primary endpoint follow-up of 48 weeks support the tested combination of the integrase inhibitor dolutegravir (Tivicay) plus the nucleoside reverse transcriptase inhibitor (RTI) lamivudine (3TC, Epivir) as an “effective option,” Pedro Cahn, MD, said at the 22nd International AIDS Conference.
The two trials from which he reported results, GEMINI-1 and GEMINI-2, which both compared the dolutegravir (DTG) plus 3TC regimen against DTG plus the nucleotide RTI tenofovir (Viread) and the nucleoside RTI emtricitabine (Emtriva), together showed after 48 weeks on treatment a 91% rate of complete virologic response to DTG plus 3TC with fewer than 50 detectable HIV RNA copies per mL, compared with a 93% complete response among patients on DTG plus tenofovir and emtricitabine. The efficacy of the two-drug regimen fell within the prespecified definition of noninferiority, compared with the three-drug comparator arm, the primary endpoint for both studies, said Dr. Cahn, scientific director of Fundacion Huesped in Buenos Aires, and professor of infectious diseases at Buenos Aires University.
“This is the first time a randomized, controlled trial showed the noninferiority of a two-drug regimen, compared with a three-drug regimen while using an integrase inhibitor as the core drug,” Dr. Cahn said. The goal of cutting the treatment regimen down to two drugs is to “reduce drug burden” and potentially produce fewer adverse effects and reduce cost, he explained.
Integrase strand transport inhibitors like DTG make sense as the core drug because “as a class they quickly reduce viral load” and have several other very attractive properties including good tolerability, a high barrier to resistance mutations, quick recovery of CD4 cell levels, and good adherence by patients, said Dr. Cahn. These advantages apply not only to DTG but also to other drugs in the class: raltegravir (Isentress), elvitegravir (Vitekta), and bictegravir (Biktarvy). Integrase inhibitors have been specified as part of the preferred anti-HIV regimen for most people starting HIV treatment by public health officials in several countries as well as by the World Health Organization in its 2018 revised HIV treatment recommendations.
But Dr. Cahn put a few qualifications on the findings so far for the combination of DTG and 3TC. Its durability has been tested out only to 48 weeks, although during that time no resistant HIV was seen. The studies will continue to follow the patients on dual treatment for as long as 144 weeks, he said. Also, the two-drug regimen should be considered, for the time being, only for patients who match the enrollment criteria for the GEMINI trials: Patients with a viral load no greater than 500,000 RNA copies/mL, no prior treatment, no evidence of preexisting viral resistance to any anti-HIV drugs, and no hepatitis B virus infection or need for hepatitis C virus treatment. Also there is uncertainty about the risk that women who become pregnant while on DTG have for giving birth to an infant with a neural tube defect. A recent report documented preliminary evidence for an increased risk (N Engl J Med. 2018 Jul 24. doi: 10.1056/NEJMc180765).
In addition to its noninferior efficacy, compared with a triple-drug regimen, the dual regimen showed good safety and tolerance, with a 7% incidence of serious adverse events and a 2% rate of events leading to withdrawal of treatment, rates similar to the triple-drug arm. The dual regimen also showed less evidence for renal damage than the triple regimen, including a statistically significant smaller drop in glomerular filtration rate than the triple regimen and no spikes in urine markers of renal damage as occurred on three drugs. Two drugs also induced no increases in markers of bone metabolism, but this happened with three drugs, Dr. Cahn reported.
The combined data from the two GEMINI studies enrolled 1,433 HIV-infected patients at centers in 21 countries including several U.S. centers. Patients averaged about 33 years old, 85% were men, and more than 90% had a CD4 cell count greater than 200 cell/mL at enrollment. Eighty percent had a viral load of no more than 100,00 RNA copies/mL, and the 20% with higher viral loads were stratified in equal numbers into the two treatment arms.
The 91% and 93% virologic response rates in the two treatment arms came in the intention-to-treat analysis and correlated with similar average rises among patients in the two arms in CD4 cell counts after 48 weeks of 224-228 cell/mm3. In the per protocol analysis the virologic response rates were 93% with the dual regimen and 94% with the triple regimen
SOURCE: Cahn P et al. AIDS 2018, Abstract 13210.
REPORTING FROM AIDS 2018
Key clinical point: The reduction in HIV by dolutegravir plus lamivudine was noninferior to the reduction by dolutegravir plus tenofovir and emtricitabine.
Major finding: HIV levels became undetectable in 91% of patients on dolutegravir plus lamivudine and in 93% on dolutegravir, tenofivir, and emtricitabine.
Study details: GEMINI-1 and GEMINI-2, two identical randomized, multicenter, randomized phase 3 trials with a total of 1,433 HIV-infected patients.
Disclosures: The GEMINI-1 and -2 trials were sponsored by GlaxoSmithKline and Viiv Healthcare, the company that markets dolutegravir (Tivicay). Dr. Cahn has been an advisor to or speaker for Abbvie, Merck, and Viiv, and he has received research funding from Abbvie, Merck, Richmond, and Viiv.
Source: Cahn P et al. AIDS 2018, Abstract 13210.
On-demand and daily PrEP look similar for HIV prevention
AMSTERDAM – Episodic, “on-demand” pre-exposure prophylaxis to prevent transmission of HIV was as effective as daily pre-exposure prophylaxis in a prospective, real-world study of more than 1,100 men who have sex with men in the Paris region.
The results showed very similar performance and complete prevention of new HIV infections in both groups, data that “strengthen the case for on-demand prophylaxis as an alternative to daily PrEP [pre-exposure prophylaxis],” Jean-Michel Molina, MD, said at the 22nd International AIDS Conference.
The evidence for efficacy of on-demand PrEP, used starting a day before through a day after unprotected sex by a man uninfected by HIV, to prevent potential infection “is now good enough for clinicians to counsel people that it is equally effective as daily PrEP and the person can decide” which regimen to use, he said in an interview. “In the future, we’ll use both strategies. We want to make PrEP easy for people to use. We want alternatives so that more people use PrEP, ” said Dr. Molina, professor of infectious diseases at the University of Paris and head of infectious diseases at Saint-Louis Hospital in Paris.
However the study focused on men who have sex with men (MSM) and so the efficacy of on-demand PrEP is not proven for preventing HIV infection during heterosexual sex, including protecting women, Dr. Molina cautioned.
The on-demand PrEP regimen tested by Dr. Molina and his associates uses the same combination of 300 mg tenofovir (Viread) and 200 mg emtricitabine (Emtriva) – formulated into a single pill and marketed as Truvada – as used for daily PrEP.
For on-demand use patients take two of these pills 2-24 hours prior to their anticipated sexual activity and then 1 pill every 24 hours until the sexual activity stops, with a final pill 24 hours following the last sex event. This translates into an ideal regimen of at least 4 pills total.
The researchers first documented the efficacy of on-demand PrEP in a placebo-controlled study with 400 randomized people that showed the on-demand regimen reduced the rate of new HIV infection by 86%, compared with placebo, among MSM who had unprotected sex (N Engl J Med. 2015 Dec 3;373[23]:2237-46). They designed the current, open-label study, ANRS-PREVENIR (Prevention of HIV in Île-de-France), to further examine the efficacy of and adherence to an on-demand PrEP regimen in a real-world setting and to compare it with daily PrEP.
The study began in May 2017, with a goal of enrolling 3,000 HIV-negative MSM. As of early July 2018, the study had enrolled 1,628 people including 1,102 who had been followed for at least 3 months and for an average of 7 months, including 124 followed for at least 1 year. Participants had a choice of using PrEP in either an on-demand or daily regimen and were allowed to switch from one regimen to the other. At enrollment, 55% opted for the on-demand regimen, and during subsequent months the fraction of participants using an on-demand regimen remained at about half. Based on self-reported use of the regimen, 96% of the men who had opted for on-demand PrEP used it “correctly,” defined as taking at least one pill within 24 hours of their sex event and at least one pill within 24 hours after the event, a rate that was identical to the “correct” usage by participants who opted for daily PrEP. The only substantial difference in PrEP use between the two subgroups was that 19% of men in the on-demand group did not use PrEP prior to at least one sex event, compared with 2% of men in the daily subgroup.
“We need to better understand” why so many participants in the on-demand group failed to use PrEP, admitted Dr. Molina. He speculated that these failures to use PrEP occurred because participants had sex with partners whom they knew were not infected with HIV.
During follow-up, the researchers identified no one who became HIV infected during 949 person-years of follow-up, a level of protection from PrEP that Dr. Molina called “remarkable.” Based on the epidemiology of HIV in the Paris region he estimated that use of PrEP by the participants in the study had prevented what might have otherwise been 85 new HIV infections. During follow-up, participants completely stopped using either daily or on-demand PrEP at a rate of 1.5 discontinuations per 100 person-years.
The incidence of adverse events was similar in the two arms of the study, with no discontinuations because of adverse events, and a 4-5 per 100 person-years incidence of grade 3 or 4 adverse events and an incidence of 2 per 100 person-years of grade 3 or 4 laboratory abnormalities. “The drugs are very well tolerated,” Dr. Molina noted, and a potential reduction in adverse events is not a reason for someone to choose on-demand PrEP instead of daily use. The primary difference is a potentially smaller pill burden: People using on-demand PrEP take on average about half the number of pills as someone on daily PrEP, which could lower the cost of prophylaxis in countries or settings where the person on PrEP has financial responsibility for the drugs. This was not an issue in the current study as the pills are available to people at no charge under the French health coverage system, Dr. Molina noted.
“On-demand PrEP is a viable option. For some people on-demand makes sense,” commented Patrick Sullivan, PhD, a professor of epidemiology at Emory University in Atlanta. It can potentially reduce drug costs, an issue for many Americans, Dr. Sullivan noted in an interview. So far, however, no reported studies have documented the efficacy of on-demand PrEP in a U.S. population, he said.
On-demand PrEP has received endorsement for use by selected people at high risk for HIV infection by public health authorities in the European Union, the United Kingdom, France, Canada, and Australia, Dr. Molina said, and in late July this strategy also received endorsement in revised HIV treatment and prevention recommendations issued by the International Antiviral Society–USA (JAMA. 2018 July 24/31;320[4]:379-96).
ANRS-PREVENIR received no commercial funding. Dr. Molina has been an advisor to Gilead, Merck, Teva, and Viiv and has received research fundings from Gilead.
SOURCE: Molina J-M et al. AIDS 2018, Abstract 13278.
AMSTERDAM – Episodic, “on-demand” pre-exposure prophylaxis to prevent transmission of HIV was as effective as daily pre-exposure prophylaxis in a prospective, real-world study of more than 1,100 men who have sex with men in the Paris region.
The results showed very similar performance and complete prevention of new HIV infections in both groups, data that “strengthen the case for on-demand prophylaxis as an alternative to daily PrEP [pre-exposure prophylaxis],” Jean-Michel Molina, MD, said at the 22nd International AIDS Conference.
The evidence for efficacy of on-demand PrEP, used starting a day before through a day after unprotected sex by a man uninfected by HIV, to prevent potential infection “is now good enough for clinicians to counsel people that it is equally effective as daily PrEP and the person can decide” which regimen to use, he said in an interview. “In the future, we’ll use both strategies. We want to make PrEP easy for people to use. We want alternatives so that more people use PrEP, ” said Dr. Molina, professor of infectious diseases at the University of Paris and head of infectious diseases at Saint-Louis Hospital in Paris.
However the study focused on men who have sex with men (MSM) and so the efficacy of on-demand PrEP is not proven for preventing HIV infection during heterosexual sex, including protecting women, Dr. Molina cautioned.
The on-demand PrEP regimen tested by Dr. Molina and his associates uses the same combination of 300 mg tenofovir (Viread) and 200 mg emtricitabine (Emtriva) – formulated into a single pill and marketed as Truvada – as used for daily PrEP.
For on-demand use patients take two of these pills 2-24 hours prior to their anticipated sexual activity and then 1 pill every 24 hours until the sexual activity stops, with a final pill 24 hours following the last sex event. This translates into an ideal regimen of at least 4 pills total.
The researchers first documented the efficacy of on-demand PrEP in a placebo-controlled study with 400 randomized people that showed the on-demand regimen reduced the rate of new HIV infection by 86%, compared with placebo, among MSM who had unprotected sex (N Engl J Med. 2015 Dec 3;373[23]:2237-46). They designed the current, open-label study, ANRS-PREVENIR (Prevention of HIV in Île-de-France), to further examine the efficacy of and adherence to an on-demand PrEP regimen in a real-world setting and to compare it with daily PrEP.
The study began in May 2017, with a goal of enrolling 3,000 HIV-negative MSM. As of early July 2018, the study had enrolled 1,628 people including 1,102 who had been followed for at least 3 months and for an average of 7 months, including 124 followed for at least 1 year. Participants had a choice of using PrEP in either an on-demand or daily regimen and were allowed to switch from one regimen to the other. At enrollment, 55% opted for the on-demand regimen, and during subsequent months the fraction of participants using an on-demand regimen remained at about half. Based on self-reported use of the regimen, 96% of the men who had opted for on-demand PrEP used it “correctly,” defined as taking at least one pill within 24 hours of their sex event and at least one pill within 24 hours after the event, a rate that was identical to the “correct” usage by participants who opted for daily PrEP. The only substantial difference in PrEP use between the two subgroups was that 19% of men in the on-demand group did not use PrEP prior to at least one sex event, compared with 2% of men in the daily subgroup.
“We need to better understand” why so many participants in the on-demand group failed to use PrEP, admitted Dr. Molina. He speculated that these failures to use PrEP occurred because participants had sex with partners whom they knew were not infected with HIV.
During follow-up, the researchers identified no one who became HIV infected during 949 person-years of follow-up, a level of protection from PrEP that Dr. Molina called “remarkable.” Based on the epidemiology of HIV in the Paris region he estimated that use of PrEP by the participants in the study had prevented what might have otherwise been 85 new HIV infections. During follow-up, participants completely stopped using either daily or on-demand PrEP at a rate of 1.5 discontinuations per 100 person-years.
The incidence of adverse events was similar in the two arms of the study, with no discontinuations because of adverse events, and a 4-5 per 100 person-years incidence of grade 3 or 4 adverse events and an incidence of 2 per 100 person-years of grade 3 or 4 laboratory abnormalities. “The drugs are very well tolerated,” Dr. Molina noted, and a potential reduction in adverse events is not a reason for someone to choose on-demand PrEP instead of daily use. The primary difference is a potentially smaller pill burden: People using on-demand PrEP take on average about half the number of pills as someone on daily PrEP, which could lower the cost of prophylaxis in countries or settings where the person on PrEP has financial responsibility for the drugs. This was not an issue in the current study as the pills are available to people at no charge under the French health coverage system, Dr. Molina noted.
“On-demand PrEP is a viable option. For some people on-demand makes sense,” commented Patrick Sullivan, PhD, a professor of epidemiology at Emory University in Atlanta. It can potentially reduce drug costs, an issue for many Americans, Dr. Sullivan noted in an interview. So far, however, no reported studies have documented the efficacy of on-demand PrEP in a U.S. population, he said.
On-demand PrEP has received endorsement for use by selected people at high risk for HIV infection by public health authorities in the European Union, the United Kingdom, France, Canada, and Australia, Dr. Molina said, and in late July this strategy also received endorsement in revised HIV treatment and prevention recommendations issued by the International Antiviral Society–USA (JAMA. 2018 July 24/31;320[4]:379-96).
ANRS-PREVENIR received no commercial funding. Dr. Molina has been an advisor to Gilead, Merck, Teva, and Viiv and has received research fundings from Gilead.
SOURCE: Molina J-M et al. AIDS 2018, Abstract 13278.
AMSTERDAM – Episodic, “on-demand” pre-exposure prophylaxis to prevent transmission of HIV was as effective as daily pre-exposure prophylaxis in a prospective, real-world study of more than 1,100 men who have sex with men in the Paris region.
The results showed very similar performance and complete prevention of new HIV infections in both groups, data that “strengthen the case for on-demand prophylaxis as an alternative to daily PrEP [pre-exposure prophylaxis],” Jean-Michel Molina, MD, said at the 22nd International AIDS Conference.
The evidence for efficacy of on-demand PrEP, used starting a day before through a day after unprotected sex by a man uninfected by HIV, to prevent potential infection “is now good enough for clinicians to counsel people that it is equally effective as daily PrEP and the person can decide” which regimen to use, he said in an interview. “In the future, we’ll use both strategies. We want to make PrEP easy for people to use. We want alternatives so that more people use PrEP, ” said Dr. Molina, professor of infectious diseases at the University of Paris and head of infectious diseases at Saint-Louis Hospital in Paris.
However the study focused on men who have sex with men (MSM) and so the efficacy of on-demand PrEP is not proven for preventing HIV infection during heterosexual sex, including protecting women, Dr. Molina cautioned.
The on-demand PrEP regimen tested by Dr. Molina and his associates uses the same combination of 300 mg tenofovir (Viread) and 200 mg emtricitabine (Emtriva) – formulated into a single pill and marketed as Truvada – as used for daily PrEP.
For on-demand use patients take two of these pills 2-24 hours prior to their anticipated sexual activity and then 1 pill every 24 hours until the sexual activity stops, with a final pill 24 hours following the last sex event. This translates into an ideal regimen of at least 4 pills total.
The researchers first documented the efficacy of on-demand PrEP in a placebo-controlled study with 400 randomized people that showed the on-demand regimen reduced the rate of new HIV infection by 86%, compared with placebo, among MSM who had unprotected sex (N Engl J Med. 2015 Dec 3;373[23]:2237-46). They designed the current, open-label study, ANRS-PREVENIR (Prevention of HIV in Île-de-France), to further examine the efficacy of and adherence to an on-demand PrEP regimen in a real-world setting and to compare it with daily PrEP.
The study began in May 2017, with a goal of enrolling 3,000 HIV-negative MSM. As of early July 2018, the study had enrolled 1,628 people including 1,102 who had been followed for at least 3 months and for an average of 7 months, including 124 followed for at least 1 year. Participants had a choice of using PrEP in either an on-demand or daily regimen and were allowed to switch from one regimen to the other. At enrollment, 55% opted for the on-demand regimen, and during subsequent months the fraction of participants using an on-demand regimen remained at about half. Based on self-reported use of the regimen, 96% of the men who had opted for on-demand PrEP used it “correctly,” defined as taking at least one pill within 24 hours of their sex event and at least one pill within 24 hours after the event, a rate that was identical to the “correct” usage by participants who opted for daily PrEP. The only substantial difference in PrEP use between the two subgroups was that 19% of men in the on-demand group did not use PrEP prior to at least one sex event, compared with 2% of men in the daily subgroup.
“We need to better understand” why so many participants in the on-demand group failed to use PrEP, admitted Dr. Molina. He speculated that these failures to use PrEP occurred because participants had sex with partners whom they knew were not infected with HIV.
During follow-up, the researchers identified no one who became HIV infected during 949 person-years of follow-up, a level of protection from PrEP that Dr. Molina called “remarkable.” Based on the epidemiology of HIV in the Paris region he estimated that use of PrEP by the participants in the study had prevented what might have otherwise been 85 new HIV infections. During follow-up, participants completely stopped using either daily or on-demand PrEP at a rate of 1.5 discontinuations per 100 person-years.
The incidence of adverse events was similar in the two arms of the study, with no discontinuations because of adverse events, and a 4-5 per 100 person-years incidence of grade 3 or 4 adverse events and an incidence of 2 per 100 person-years of grade 3 or 4 laboratory abnormalities. “The drugs are very well tolerated,” Dr. Molina noted, and a potential reduction in adverse events is not a reason for someone to choose on-demand PrEP instead of daily use. The primary difference is a potentially smaller pill burden: People using on-demand PrEP take on average about half the number of pills as someone on daily PrEP, which could lower the cost of prophylaxis in countries or settings where the person on PrEP has financial responsibility for the drugs. This was not an issue in the current study as the pills are available to people at no charge under the French health coverage system, Dr. Molina noted.
“On-demand PrEP is a viable option. For some people on-demand makes sense,” commented Patrick Sullivan, PhD, a professor of epidemiology at Emory University in Atlanta. It can potentially reduce drug costs, an issue for many Americans, Dr. Sullivan noted in an interview. So far, however, no reported studies have documented the efficacy of on-demand PrEP in a U.S. population, he said.
On-demand PrEP has received endorsement for use by selected people at high risk for HIV infection by public health authorities in the European Union, the United Kingdom, France, Canada, and Australia, Dr. Molina said, and in late July this strategy also received endorsement in revised HIV treatment and prevention recommendations issued by the International Antiviral Society–USA (JAMA. 2018 July 24/31;320[4]:379-96).
ANRS-PREVENIR received no commercial funding. Dr. Molina has been an advisor to Gilead, Merck, Teva, and Viiv and has received research fundings from Gilead.
SOURCE: Molina J-M et al. AIDS 2018, Abstract 13278.
REPORTING FROM AIDS 2018
Key clinical point:
Major finding: Men using on-demand PrEP had no HIV infections during an average 7 months of follow-up.
Study details: ANRS-PREVENIR, a prospective, multicenter, open-label study with 1,102 people followed for at least 3 months.
Disclosures: ANRS-PREVENIR received no commercial funding. Dr. Molina has been an advisor to Gilead, Merck, Teva, and Viiv and has received research fundings from Gilead.
Source: Molina J-M et al. AIDS 2018, Abstract 13278.
Rising U.S. PrEP use linked with dropping HIV infections
AMSTERDAM – Preexposure prophylaxis (PrEP) against HIV infection by U.S. residents appears to be paying off: The number of new U.S. HIV infections among those at least 13 years old dropped during 2012-2016, and this decline showed a statistically significant link with growth in drug prophylaxis among U.S. residents during the same time.
Uptake of HIV PrEP “was significantly associated with declines in HIV diagnoses in the United States, independent of levels of viral suppression,” Patrick S. Sullivan, Ph.D., and his associates said in a poster presented at the 22nd International AIDS Conference.
Their analysis of nationwide U.S. data showed that during 2012-2016 new HIV diagnoses in residents at least 13 years old fell by an estimated annual percent change of 4.65 among the 10 states with the greatest rate of PrEP use by residents, compared with increases in the estimated annual percent change in new HIV diagnoses of about 1-1.5 in the 14 states with the lowest PrEP use. This statistically significant link remained after adjusting for variations in levels of viral suppression among HIV-infected residents in each state, another factor driving reduced infection rates, Dr. Sullivan and his associates reported..
In the ten-state subgroup with the greatest PrEP uptake, use of PrEP in people at risk for HIV rose from 12/1,000 people in 2012, the year that the Food and Drug Administration first approved a PrEP regimen, to 110/1,000 at-risk people in 2016, a ninefold increase. PrEP use jumped by about the same relative amount in the seven states with the lowest PrEP use, but because it was only 3/1,000 people in 2012 it reached only 35/1,000 in 2016, less than a third of the rate in the states that administered the most PrEP.
In absolute, unadjusted numbers the rate of new HIV diagnoses in the 10 states with the greatest PrEP use fell from 19.4 cases/100,000 population to 13.6/100,000 in 2016. Total U.S. HIV diagnosis rates in people at least 13 years old fell from 15.7/100,000 in 2012 to 14.5/100,000 in 2016, reported Dr. Sullivan, a professor of epidemiology at Emory University in Atlanta.
Dr. Sullivan and his coauthors cautioned that these associations do not allow inference of a causal relationship, and their data did not allow them to estimate the relative contributions of PrEP uptake and HIV suppression to the declining trend in diagnosed HIV infections. However PrEP and suppressive HIV treatment act in a complimentary way to potentially drop the rate of new HIV transmissions, he said.
In the years since 2012, when the Food and Drug Administration approved PrEP as an indication for 200-mg emtricitabine (Emtriva) and 300 mg tenofovir (Viread) – formulated into a single pill and marketed as Truvada, the idea of PrEP for people at increased risk for HIV exposure has gained traction.
Awareness of, knowledge about, and uptake of PrEP have all increased among U.S. residents since a PrEP formulation became available, Dr. Sullivan said. It’s become a cultural norm in at least some communities, he said in an interview. The cost for daily PrEP has posed a barrier to some potential users, but in many U.S. settings people can find ways to at least partially subsidize the cost even when lacking insurance coverage for the drug, he noted.
To determine rates of new U.S. HIV diagnoses Dr. Sullivan and his associates used data collected by the National HIV Surveillance System. To estimate rates of PrEP uptake they used data from prescriptions filled for the emtricitabine and tenofovir formulation that they then adjusted to rule out use for indications other than PrEP (Ann Epidemiol. 2018 Jun 22. doi: 10.1016/j.annepidem.2018.06.009).
SOURCE: Sullivan PS et al. AIDS 2018, Abstract 13004.
AMSTERDAM – Preexposure prophylaxis (PrEP) against HIV infection by U.S. residents appears to be paying off: The number of new U.S. HIV infections among those at least 13 years old dropped during 2012-2016, and this decline showed a statistically significant link with growth in drug prophylaxis among U.S. residents during the same time.
Uptake of HIV PrEP “was significantly associated with declines in HIV diagnoses in the United States, independent of levels of viral suppression,” Patrick S. Sullivan, Ph.D., and his associates said in a poster presented at the 22nd International AIDS Conference.
Their analysis of nationwide U.S. data showed that during 2012-2016 new HIV diagnoses in residents at least 13 years old fell by an estimated annual percent change of 4.65 among the 10 states with the greatest rate of PrEP use by residents, compared with increases in the estimated annual percent change in new HIV diagnoses of about 1-1.5 in the 14 states with the lowest PrEP use. This statistically significant link remained after adjusting for variations in levels of viral suppression among HIV-infected residents in each state, another factor driving reduced infection rates, Dr. Sullivan and his associates reported..
In the ten-state subgroup with the greatest PrEP uptake, use of PrEP in people at risk for HIV rose from 12/1,000 people in 2012, the year that the Food and Drug Administration first approved a PrEP regimen, to 110/1,000 at-risk people in 2016, a ninefold increase. PrEP use jumped by about the same relative amount in the seven states with the lowest PrEP use, but because it was only 3/1,000 people in 2012 it reached only 35/1,000 in 2016, less than a third of the rate in the states that administered the most PrEP.
In absolute, unadjusted numbers the rate of new HIV diagnoses in the 10 states with the greatest PrEP use fell from 19.4 cases/100,000 population to 13.6/100,000 in 2016. Total U.S. HIV diagnosis rates in people at least 13 years old fell from 15.7/100,000 in 2012 to 14.5/100,000 in 2016, reported Dr. Sullivan, a professor of epidemiology at Emory University in Atlanta.
Dr. Sullivan and his coauthors cautioned that these associations do not allow inference of a causal relationship, and their data did not allow them to estimate the relative contributions of PrEP uptake and HIV suppression to the declining trend in diagnosed HIV infections. However PrEP and suppressive HIV treatment act in a complimentary way to potentially drop the rate of new HIV transmissions, he said.
In the years since 2012, when the Food and Drug Administration approved PrEP as an indication for 200-mg emtricitabine (Emtriva) and 300 mg tenofovir (Viread) – formulated into a single pill and marketed as Truvada, the idea of PrEP for people at increased risk for HIV exposure has gained traction.
Awareness of, knowledge about, and uptake of PrEP have all increased among U.S. residents since a PrEP formulation became available, Dr. Sullivan said. It’s become a cultural norm in at least some communities, he said in an interview. The cost for daily PrEP has posed a barrier to some potential users, but in many U.S. settings people can find ways to at least partially subsidize the cost even when lacking insurance coverage for the drug, he noted.
To determine rates of new U.S. HIV diagnoses Dr. Sullivan and his associates used data collected by the National HIV Surveillance System. To estimate rates of PrEP uptake they used data from prescriptions filled for the emtricitabine and tenofovir formulation that they then adjusted to rule out use for indications other than PrEP (Ann Epidemiol. 2018 Jun 22. doi: 10.1016/j.annepidem.2018.06.009).
SOURCE: Sullivan PS et al. AIDS 2018, Abstract 13004.
AMSTERDAM – Preexposure prophylaxis (PrEP) against HIV infection by U.S. residents appears to be paying off: The number of new U.S. HIV infections among those at least 13 years old dropped during 2012-2016, and this decline showed a statistically significant link with growth in drug prophylaxis among U.S. residents during the same time.
Uptake of HIV PrEP “was significantly associated with declines in HIV diagnoses in the United States, independent of levels of viral suppression,” Patrick S. Sullivan, Ph.D., and his associates said in a poster presented at the 22nd International AIDS Conference.
Their analysis of nationwide U.S. data showed that during 2012-2016 new HIV diagnoses in residents at least 13 years old fell by an estimated annual percent change of 4.65 among the 10 states with the greatest rate of PrEP use by residents, compared with increases in the estimated annual percent change in new HIV diagnoses of about 1-1.5 in the 14 states with the lowest PrEP use. This statistically significant link remained after adjusting for variations in levels of viral suppression among HIV-infected residents in each state, another factor driving reduced infection rates, Dr. Sullivan and his associates reported..
In the ten-state subgroup with the greatest PrEP uptake, use of PrEP in people at risk for HIV rose from 12/1,000 people in 2012, the year that the Food and Drug Administration first approved a PrEP regimen, to 110/1,000 at-risk people in 2016, a ninefold increase. PrEP use jumped by about the same relative amount in the seven states with the lowest PrEP use, but because it was only 3/1,000 people in 2012 it reached only 35/1,000 in 2016, less than a third of the rate in the states that administered the most PrEP.
In absolute, unadjusted numbers the rate of new HIV diagnoses in the 10 states with the greatest PrEP use fell from 19.4 cases/100,000 population to 13.6/100,000 in 2016. Total U.S. HIV diagnosis rates in people at least 13 years old fell from 15.7/100,000 in 2012 to 14.5/100,000 in 2016, reported Dr. Sullivan, a professor of epidemiology at Emory University in Atlanta.
Dr. Sullivan and his coauthors cautioned that these associations do not allow inference of a causal relationship, and their data did not allow them to estimate the relative contributions of PrEP uptake and HIV suppression to the declining trend in diagnosed HIV infections. However PrEP and suppressive HIV treatment act in a complimentary way to potentially drop the rate of new HIV transmissions, he said.
In the years since 2012, when the Food and Drug Administration approved PrEP as an indication for 200-mg emtricitabine (Emtriva) and 300 mg tenofovir (Viread) – formulated into a single pill and marketed as Truvada, the idea of PrEP for people at increased risk for HIV exposure has gained traction.
Awareness of, knowledge about, and uptake of PrEP have all increased among U.S. residents since a PrEP formulation became available, Dr. Sullivan said. It’s become a cultural norm in at least some communities, he said in an interview. The cost for daily PrEP has posed a barrier to some potential users, but in many U.S. settings people can find ways to at least partially subsidize the cost even when lacking insurance coverage for the drug, he noted.
To determine rates of new U.S. HIV diagnoses Dr. Sullivan and his associates used data collected by the National HIV Surveillance System. To estimate rates of PrEP uptake they used data from prescriptions filled for the emtricitabine and tenofovir formulation that they then adjusted to rule out use for indications other than PrEP (Ann Epidemiol. 2018 Jun 22. doi: 10.1016/j.annepidem.2018.06.009).
SOURCE: Sullivan PS et al. AIDS 2018, Abstract 13004.
REPORTING FROM AIDS 2018
Key clinical Rising use of PrEP to prevent HIV infection since 2012 is linked with a drop in new U.S. HIV infections.
Major finding: In 10 states with the highest PrEP use new HIV infections fell by an estimated annual percent change of 4.65.
Study details: Analysis of U.S. national data during 2012-2016.
Disclosures: The study was funded by Gilead, the company that markets emtricitabine and tenofovir (Truvada). Dr. Sullivan had no disclosures. Two coauthors on the study were Gilead employees.
Source: Sullivan PS et al. AIDS 2018, Abstract 13004.
‘Undetectable’ HIV means ‘untransmissible’ confirmed in larger sex study
AMSTERDAM – One maxim of current HIV management is U=U; Undetectable equals Untransmissible, and it received new backing for the specific question of whether HIV treated to an undetectable level can transmit from a man who engages in condomless anal sex to an uninfected man. The answer was it effectively could not.
In nearly 77,000 sexual encounters of this type performed during a median 1.6 years of follow-up of each participating couple, no episodes resulted in HIV transmission. When researchers combined the new findings with numbers from a smaller, earlier study they ran of similar male couples the statistics showed a worst case of at most one HIV transmission for every 435 person years of follow-up, or “effectively zero,” Alison Rodger, MD, said at the 22nd International AIDS Conference.
“The evidence is very robust. Transmission simply does not occur,” said Dr. Rodger, an infectious disease physician and clinical director of public health at the Royal Free Hospital in London. She cautioned, however, that the finding occurred in couples where the HIV-infected partner consistently had a serum viral load of less than 200 copies of HIV RNA/mL when tested at the start and the end of follow-up and at various times in between. The researchers censored data from couples when the infected partner had a detectable viral load.
The PARTNER-2 (Partners of People on ART – A New Evaluation of the Risks) study followed the PARTNER-1 study that had examined the same question of HIV transmissibility when undetectable during sexual encounters but with a much smaller number of men who have sex with men (JAMA. 2016 July 12;316[2]:171-81). PARTNER-2 enrolled 783 male couples from any of 12 European countries that contributed 1,596 years of couple follow-up. During the median 1.6 years of follow-up per couple, one or both partners had a different sexually transmitted disease 23%-27% of the time, and 37% of the HIV-negative partners had condomless sex with a different partner. The couples averaged 43 sexual encounters a year that produced an overall total of 76,991. During follow-up, 15 of the HIV-negative partners become HIV positive, but in all 15 cases the source of the infection was genetically proven to have come from someone other than the index partner.
Based on the number of sex events studies Dr. Rodger and her associates calculated the 95% confidence interval around the zero transmissions they observed during gay male sex events with undetectable HIV in both PARTNER-2 and PARTNER-1. The upper bound of this confidence interval was a rate of 0.23 transmissions per 100 person years of follow-up,
In other words, the scope of the two combined studies cannot statistically rule out a worst-case scenario of one transmission for every 435 person years of follow-up, or for every 18,696 sex events of the type studied. However, “we’ve made the confidence much more robust. We can’t say it’s zero risk, but it’s effectively zero,” Dr. Rodger said in an interview. “You could keep studying this forever” to further rule out the risk for transmission of undetectable HIV, “but I think the question is now settled,” she declared. She also stressed that condom use remained important to prevent other sexually transmitted diseases.
SOURCE: Rodger A et al. AIDS 2018, Abstract 13470.
AMSTERDAM – One maxim of current HIV management is U=U; Undetectable equals Untransmissible, and it received new backing for the specific question of whether HIV treated to an undetectable level can transmit from a man who engages in condomless anal sex to an uninfected man. The answer was it effectively could not.
In nearly 77,000 sexual encounters of this type performed during a median 1.6 years of follow-up of each participating couple, no episodes resulted in HIV transmission. When researchers combined the new findings with numbers from a smaller, earlier study they ran of similar male couples the statistics showed a worst case of at most one HIV transmission for every 435 person years of follow-up, or “effectively zero,” Alison Rodger, MD, said at the 22nd International AIDS Conference.
“The evidence is very robust. Transmission simply does not occur,” said Dr. Rodger, an infectious disease physician and clinical director of public health at the Royal Free Hospital in London. She cautioned, however, that the finding occurred in couples where the HIV-infected partner consistently had a serum viral load of less than 200 copies of HIV RNA/mL when tested at the start and the end of follow-up and at various times in between. The researchers censored data from couples when the infected partner had a detectable viral load.
The PARTNER-2 (Partners of People on ART – A New Evaluation of the Risks) study followed the PARTNER-1 study that had examined the same question of HIV transmissibility when undetectable during sexual encounters but with a much smaller number of men who have sex with men (JAMA. 2016 July 12;316[2]:171-81). PARTNER-2 enrolled 783 male couples from any of 12 European countries that contributed 1,596 years of couple follow-up. During the median 1.6 years of follow-up per couple, one or both partners had a different sexually transmitted disease 23%-27% of the time, and 37% of the HIV-negative partners had condomless sex with a different partner. The couples averaged 43 sexual encounters a year that produced an overall total of 76,991. During follow-up, 15 of the HIV-negative partners become HIV positive, but in all 15 cases the source of the infection was genetically proven to have come from someone other than the index partner.
Based on the number of sex events studies Dr. Rodger and her associates calculated the 95% confidence interval around the zero transmissions they observed during gay male sex events with undetectable HIV in both PARTNER-2 and PARTNER-1. The upper bound of this confidence interval was a rate of 0.23 transmissions per 100 person years of follow-up,
In other words, the scope of the two combined studies cannot statistically rule out a worst-case scenario of one transmission for every 435 person years of follow-up, or for every 18,696 sex events of the type studied. However, “we’ve made the confidence much more robust. We can’t say it’s zero risk, but it’s effectively zero,” Dr. Rodger said in an interview. “You could keep studying this forever” to further rule out the risk for transmission of undetectable HIV, “but I think the question is now settled,” she declared. She also stressed that condom use remained important to prevent other sexually transmitted diseases.
SOURCE: Rodger A et al. AIDS 2018, Abstract 13470.
AMSTERDAM – One maxim of current HIV management is U=U; Undetectable equals Untransmissible, and it received new backing for the specific question of whether HIV treated to an undetectable level can transmit from a man who engages in condomless anal sex to an uninfected man. The answer was it effectively could not.
In nearly 77,000 sexual encounters of this type performed during a median 1.6 years of follow-up of each participating couple, no episodes resulted in HIV transmission. When researchers combined the new findings with numbers from a smaller, earlier study they ran of similar male couples the statistics showed a worst case of at most one HIV transmission for every 435 person years of follow-up, or “effectively zero,” Alison Rodger, MD, said at the 22nd International AIDS Conference.
“The evidence is very robust. Transmission simply does not occur,” said Dr. Rodger, an infectious disease physician and clinical director of public health at the Royal Free Hospital in London. She cautioned, however, that the finding occurred in couples where the HIV-infected partner consistently had a serum viral load of less than 200 copies of HIV RNA/mL when tested at the start and the end of follow-up and at various times in between. The researchers censored data from couples when the infected partner had a detectable viral load.
The PARTNER-2 (Partners of People on ART – A New Evaluation of the Risks) study followed the PARTNER-1 study that had examined the same question of HIV transmissibility when undetectable during sexual encounters but with a much smaller number of men who have sex with men (JAMA. 2016 July 12;316[2]:171-81). PARTNER-2 enrolled 783 male couples from any of 12 European countries that contributed 1,596 years of couple follow-up. During the median 1.6 years of follow-up per couple, one or both partners had a different sexually transmitted disease 23%-27% of the time, and 37% of the HIV-negative partners had condomless sex with a different partner. The couples averaged 43 sexual encounters a year that produced an overall total of 76,991. During follow-up, 15 of the HIV-negative partners become HIV positive, but in all 15 cases the source of the infection was genetically proven to have come from someone other than the index partner.
Based on the number of sex events studies Dr. Rodger and her associates calculated the 95% confidence interval around the zero transmissions they observed during gay male sex events with undetectable HIV in both PARTNER-2 and PARTNER-1. The upper bound of this confidence interval was a rate of 0.23 transmissions per 100 person years of follow-up,
In other words, the scope of the two combined studies cannot statistically rule out a worst-case scenario of one transmission for every 435 person years of follow-up, or for every 18,696 sex events of the type studied. However, “we’ve made the confidence much more robust. We can’t say it’s zero risk, but it’s effectively zero,” Dr. Rodger said in an interview. “You could keep studying this forever” to further rule out the risk for transmission of undetectable HIV, “but I think the question is now settled,” she declared. She also stressed that condom use remained important to prevent other sexually transmitted diseases.
SOURCE: Rodger A et al. AIDS 2018, Abstract 13470.
REPORTING FROM AIDS 2018
Key clinical point: Undetectable HIV did not produce any transmissions during gay male sexual activity.
Major finding: During 76,991 unprotected gay male sex events no HIV transmission occurred from men with an undetectable viral load.
Study details: PARTNER-2, a prospective, multicenter study of 783 sexually active male couples.
Disclosures: PARTNER-2 received partial funding from unrestricted grants from Viiv and Gilead. Dr. Rodger had no disclosures.
Source: Rodger A et al. AIDS 2018, Abstract 13470.
People with HIV develop more frailty despite treatment
AMSTERDAM – Middle-aged and elderly people infected with HIV were more likely to meet an established definition of frailty than were uninfected people of the same age, and during 4 years of follow-up frailty significantly linked with an increased incidence of both mortality and development of new comorbidities, based on a Dutch prospective study of 1,146 people.
People living with HIV also showed, despite antiretroviral treatment, a significantly increased rate of progression to frailty over the course of 4 years, compared with uninfected people, after adjustment for demographic differences. This progression to frailty appeared mediated by a high waist-to-hip ratio, a higher number of preexisting comorbidities, and symptoms of depression, Eveline Verheij, MD, said at the 22nd International AIDS Conference.
At entry into the study, people living with HIV had a 10% prevalence of frailty, compared with 3% among those who were uninfected, said Dr. Verheij, a researcher with the Amsterdam Institute for Global Health & Development. She defined frailty using criteria first introduced by researchers in 2001, which established five characteristics as markers of frailty: slow gait, low grip strength, a low level of physical activity, self-reported exhaustion, and unintentional weight loss of at least 10 pounds during the preceding year (J Gerontol A Biol Sci Med. 2001 Mar 1;56[3]:M146-57).
People with three or more of these conditions were identified as frail, those with one or two were tagged as prefrail, and people with none of these five characteristics were considered robust.
In the study reported by Dr. Verheij, the prevalence of people identified as robust at the time they entered the study was about 60% of those without an HIV infection and about 40% of those infected with HIV. During the 4 years she and her associates followed these people, their rates of progression from a robust state to frailty occurred more than twice as often among the people living with HIV, compared with those who were uninfected, after adjustment for age, ethnicity, and education.
Dr. Verheij admitted that she and her associates have not identified interventions that are effective for reversing frailty. “People who are already frail are likely to remain frail,” she noted. A better strategy is to take steps to defer frailty and help people who are robust retain that status. This could involve measures such as smoking cessation, exercise, and maintaining or expanding social networks, she suggested.
The AGEhiV Cohort Study enrolled 596 people living with HIV and 550 uninfected people who were all at least 45 years old. The average age was 52 years, with about 10% in each group older than 65 years. About 90% of the enrollees were Dutch, nearly three-quarters of those in both groups were men who have sex with men, and 14% of those who were uninfected and 20% of those living with HIV had symptoms of depression.
At baseline, 61% of those without HIV and 48% of people with HIV had no comorbidities, and while the percentage in both groups with one comorbidity at entry was nearly the same, 28% and 31%, respectively, the percentage with two or more comorbidities was more divergent. Among those without HIV infection, 8% had two comorbidities and 3% had three or more, while among those with HIV, 14% had two comorbidities and 6% had three or more.
The people living with HIV had been infected for an average of 12 years. At enrollment, 96% were on antiretroviral therapy, and those on treatment had received it for an average of 10 years. At enrollment, their average CD4 cell count was 565 cells/mm3. Their average nadir cell count had been 170 cells/mm3, and 32% had a history of being diagnosed with AIDS.
Dr. Verheij and her associates examined each participant at baseline and twice more, 2 and 4 years after enrollment. During the 4 years of follow-up, 17 people died. After adjustment for age, baseline comorbidities, and HIV infection, the mortality was more than 10-fold higher among people who had been frail at entry, compared with those who were robust.
During follow-up, 276 of all enrollees developed 329 comorbidities. The four most common incident comorbidities were hypertension, followed by chronic obstructive lung disease, renal insufficiency, and osteoporosis. These four conditions accounted for three-quarters of all incident comorbidities. After adjustment for demographics, baseline comorbidities, and HIV status, people who entered the study as frail or who became frail during the study had about a 90% increased rate of developing a new comorbidity compared with those who were not frail.
SOURCE: Verheij E et al. AIDS 2018, Abstract 9303, THAB01015.
AMSTERDAM – Middle-aged and elderly people infected with HIV were more likely to meet an established definition of frailty than were uninfected people of the same age, and during 4 years of follow-up frailty significantly linked with an increased incidence of both mortality and development of new comorbidities, based on a Dutch prospective study of 1,146 people.
People living with HIV also showed, despite antiretroviral treatment, a significantly increased rate of progression to frailty over the course of 4 years, compared with uninfected people, after adjustment for demographic differences. This progression to frailty appeared mediated by a high waist-to-hip ratio, a higher number of preexisting comorbidities, and symptoms of depression, Eveline Verheij, MD, said at the 22nd International AIDS Conference.
At entry into the study, people living with HIV had a 10% prevalence of frailty, compared with 3% among those who were uninfected, said Dr. Verheij, a researcher with the Amsterdam Institute for Global Health & Development. She defined frailty using criteria first introduced by researchers in 2001, which established five characteristics as markers of frailty: slow gait, low grip strength, a low level of physical activity, self-reported exhaustion, and unintentional weight loss of at least 10 pounds during the preceding year (J Gerontol A Biol Sci Med. 2001 Mar 1;56[3]:M146-57).
People with three or more of these conditions were identified as frail, those with one or two were tagged as prefrail, and people with none of these five characteristics were considered robust.
In the study reported by Dr. Verheij, the prevalence of people identified as robust at the time they entered the study was about 60% of those without an HIV infection and about 40% of those infected with HIV. During the 4 years she and her associates followed these people, their rates of progression from a robust state to frailty occurred more than twice as often among the people living with HIV, compared with those who were uninfected, after adjustment for age, ethnicity, and education.
Dr. Verheij admitted that she and her associates have not identified interventions that are effective for reversing frailty. “People who are already frail are likely to remain frail,” she noted. A better strategy is to take steps to defer frailty and help people who are robust retain that status. This could involve measures such as smoking cessation, exercise, and maintaining or expanding social networks, she suggested.
The AGEhiV Cohort Study enrolled 596 people living with HIV and 550 uninfected people who were all at least 45 years old. The average age was 52 years, with about 10% in each group older than 65 years. About 90% of the enrollees were Dutch, nearly three-quarters of those in both groups were men who have sex with men, and 14% of those who were uninfected and 20% of those living with HIV had symptoms of depression.
At baseline, 61% of those without HIV and 48% of people with HIV had no comorbidities, and while the percentage in both groups with one comorbidity at entry was nearly the same, 28% and 31%, respectively, the percentage with two or more comorbidities was more divergent. Among those without HIV infection, 8% had two comorbidities and 3% had three or more, while among those with HIV, 14% had two comorbidities and 6% had three or more.
The people living with HIV had been infected for an average of 12 years. At enrollment, 96% were on antiretroviral therapy, and those on treatment had received it for an average of 10 years. At enrollment, their average CD4 cell count was 565 cells/mm3. Their average nadir cell count had been 170 cells/mm3, and 32% had a history of being diagnosed with AIDS.
Dr. Verheij and her associates examined each participant at baseline and twice more, 2 and 4 years after enrollment. During the 4 years of follow-up, 17 people died. After adjustment for age, baseline comorbidities, and HIV infection, the mortality was more than 10-fold higher among people who had been frail at entry, compared with those who were robust.
During follow-up, 276 of all enrollees developed 329 comorbidities. The four most common incident comorbidities were hypertension, followed by chronic obstructive lung disease, renal insufficiency, and osteoporosis. These four conditions accounted for three-quarters of all incident comorbidities. After adjustment for demographics, baseline comorbidities, and HIV status, people who entered the study as frail or who became frail during the study had about a 90% increased rate of developing a new comorbidity compared with those who were not frail.
SOURCE: Verheij E et al. AIDS 2018, Abstract 9303, THAB01015.
AMSTERDAM – Middle-aged and elderly people infected with HIV were more likely to meet an established definition of frailty than were uninfected people of the same age, and during 4 years of follow-up frailty significantly linked with an increased incidence of both mortality and development of new comorbidities, based on a Dutch prospective study of 1,146 people.
People living with HIV also showed, despite antiretroviral treatment, a significantly increased rate of progression to frailty over the course of 4 years, compared with uninfected people, after adjustment for demographic differences. This progression to frailty appeared mediated by a high waist-to-hip ratio, a higher number of preexisting comorbidities, and symptoms of depression, Eveline Verheij, MD, said at the 22nd International AIDS Conference.
At entry into the study, people living with HIV had a 10% prevalence of frailty, compared with 3% among those who were uninfected, said Dr. Verheij, a researcher with the Amsterdam Institute for Global Health & Development. She defined frailty using criteria first introduced by researchers in 2001, which established five characteristics as markers of frailty: slow gait, low grip strength, a low level of physical activity, self-reported exhaustion, and unintentional weight loss of at least 10 pounds during the preceding year (J Gerontol A Biol Sci Med. 2001 Mar 1;56[3]:M146-57).
People with three or more of these conditions were identified as frail, those with one or two were tagged as prefrail, and people with none of these five characteristics were considered robust.
In the study reported by Dr. Verheij, the prevalence of people identified as robust at the time they entered the study was about 60% of those without an HIV infection and about 40% of those infected with HIV. During the 4 years she and her associates followed these people, their rates of progression from a robust state to frailty occurred more than twice as often among the people living with HIV, compared with those who were uninfected, after adjustment for age, ethnicity, and education.
Dr. Verheij admitted that she and her associates have not identified interventions that are effective for reversing frailty. “People who are already frail are likely to remain frail,” she noted. A better strategy is to take steps to defer frailty and help people who are robust retain that status. This could involve measures such as smoking cessation, exercise, and maintaining or expanding social networks, she suggested.
The AGEhiV Cohort Study enrolled 596 people living with HIV and 550 uninfected people who were all at least 45 years old. The average age was 52 years, with about 10% in each group older than 65 years. About 90% of the enrollees were Dutch, nearly three-quarters of those in both groups were men who have sex with men, and 14% of those who were uninfected and 20% of those living with HIV had symptoms of depression.
At baseline, 61% of those without HIV and 48% of people with HIV had no comorbidities, and while the percentage in both groups with one comorbidity at entry was nearly the same, 28% and 31%, respectively, the percentage with two or more comorbidities was more divergent. Among those without HIV infection, 8% had two comorbidities and 3% had three or more, while among those with HIV, 14% had two comorbidities and 6% had three or more.
The people living with HIV had been infected for an average of 12 years. At enrollment, 96% were on antiretroviral therapy, and those on treatment had received it for an average of 10 years. At enrollment, their average CD4 cell count was 565 cells/mm3. Their average nadir cell count had been 170 cells/mm3, and 32% had a history of being diagnosed with AIDS.
Dr. Verheij and her associates examined each participant at baseline and twice more, 2 and 4 years after enrollment. During the 4 years of follow-up, 17 people died. After adjustment for age, baseline comorbidities, and HIV infection, the mortality was more than 10-fold higher among people who had been frail at entry, compared with those who were robust.
During follow-up, 276 of all enrollees developed 329 comorbidities. The four most common incident comorbidities were hypertension, followed by chronic obstructive lung disease, renal insufficiency, and osteoporosis. These four conditions accounted for three-quarters of all incident comorbidities. After adjustment for demographics, baseline comorbidities, and HIV status, people who entered the study as frail or who became frail during the study had about a 90% increased rate of developing a new comorbidity compared with those who were not frail.
SOURCE: Verheij E et al. AIDS 2018, Abstract 9303, THAB01015.
REPORTING FROM AIDS 2018
Key clinical point: HIV infection links with a higher prevalence and incidence of frailty.
Major finding: At study entry, frailty was present in 10% of HIV-infected people and in 3% of those without HIV.
Study details: AGEhiV Cohort Study, a single-center study of 1,146 people.
Disclosures: The AGEhiV Cohort Study received no commercial funding. Dr. Verheij had no disclosures.
Source: Verheij E et al. AIDS 2018, Abstract 9303, THAB01015.
Incident heart failure linked to HIV infection
AMSTERDAM –
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“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.
SOURCE: Go AS et al. AIDS 2018, Abstract 2778, THAB0103.
AMSTERDAM –
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“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.
SOURCE: Go AS et al. AIDS 2018, Abstract 2778, THAB0103.
AMSTERDAM –
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“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.
SOURCE: Go AS et al. AIDS 2018, Abstract 2778, THAB0103.
REPORTING FROM AIDS 2018
Key clinical point: HIV infection may be an independent trigger for heart failure.
Major finding: After extensive adjustment for potential confounders, HIV infection linked with a 66% increased rate of incident heart failure.
Study details: The Kaiser Permanente HIV Heart Study, which included medical records for 425,454 people.
Disclosures: Dr. Go had no disclosures.
Source: Go AS et al. AIDS 2018, Abstract 2778, THAB0103.
Novel HIV vaccine induces durable immune responses
AMSTERDAM – 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.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“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.
SOURCE: Tomaka FL et al. AIDS 2018, Abstract TUAA0104.
The 1-year results for this new HIV vaccine and now the 1-year follow-up results appear very promising for its future prospects in wider clinical testing.
What’s especially interesting about the data reported for this vaccine so far is that the developers also tested the vaccine in rhesus monkeys and showed similar immunologic induction and a 67% efficacy for protecting against repeated challenges with a simian-human immunodeficiency virus. This level of protection against infection and the similar cellular and antibody responses to the vaccine and booster in the animal model and in people is encouraging. The vaccine protected monkeys. Now we need to find out whether it will protect humans.
R. Brad Jones, PhD , is an immunologist at Cornell University, New York. He had no disclosures. He made these comments during a talk at the conference.
The 1-year results for this new HIV vaccine and now the 1-year follow-up results appear very promising for its future prospects in wider clinical testing.
What’s especially interesting about the data reported for this vaccine so far is that the developers also tested the vaccine in rhesus monkeys and showed similar immunologic induction and a 67% efficacy for protecting against repeated challenges with a simian-human immunodeficiency virus. This level of protection against infection and the similar cellular and antibody responses to the vaccine and booster in the animal model and in people is encouraging. The vaccine protected monkeys. Now we need to find out whether it will protect humans.
R. Brad Jones, PhD , is an immunologist at Cornell University, New York. He had no disclosures. He made these comments during a talk at the conference.
The 1-year results for this new HIV vaccine and now the 1-year follow-up results appear very promising for its future prospects in wider clinical testing.
What’s especially interesting about the data reported for this vaccine so far is that the developers also tested the vaccine in rhesus monkeys and showed similar immunologic induction and a 67% efficacy for protecting against repeated challenges with a simian-human immunodeficiency virus. This level of protection against infection and the similar cellular and antibody responses to the vaccine and booster in the animal model and in people is encouraging. The vaccine protected monkeys. Now we need to find out whether it will protect humans.
R. Brad Jones, PhD , is an immunologist at Cornell University, New York. He had no disclosures. He made these comments during a talk at the conference.
AMSTERDAM – 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.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“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.
SOURCE: Tomaka FL et al. AIDS 2018, Abstract TUAA0104.
AMSTERDAM – 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.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“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.
SOURCE: Tomaka FL et al. AIDS 2018, Abstract TUAA0104.
REPORTING FROM AIDS 2018
Key clinical point: An investigational HIV vaccine and booster showed durable safety and anti-HIV immune effects.
Major finding: One year follow-up after the final dosage showed no serious or grade 3 or 4 adverse effects and durable immune responses.
Study details: The APPROACH study, a phase I/IIa study with 393 participants.
Disclosures: APPROACH was sponsored by Janssen, the company developing the vaccine. Dr. Tomaka is a Janssen employee.
Source: Tomaka FL et al. AIDS 2018, Abstract TUAA0104.
HIV infection linked with doubled stroke rate
AMSTERDAM – Patients infected with HIV had a roughly doubled rate of stroke compared with the general population, based on analysis of data collected from about 23 million people in Taiwan – including nearly 6,000 with HIV infection.
The combined rate of both ischemic and hemorrhagic stroke was especially elevated during the first 7 years after a diagnosis of HIV positivity, with a nearly 47-fold increased incidence rate during the first year following HIV diagnosis compared with the general age- and sex-adjusted general population, and a nearly fourfold increased rate during years 1-7, both statistically significant differences, Hui-Lin Lin, MD, reported in a poster at the 22nd International AIDS Conference.
Once the period studied reached 8 or more years out from the time of HIV diagnosis, infected patients showed no statistically significant difference in their stroke rate compared with the general population. For the entire follow-up, the stroke rate was 94% higher among HIV-infected patients compared with the general population, a statistically significant difference.
HIV-infected patients who had a stroke also developed it at a much younger age than did the general population. The median age of the infected patients with a stroke was 49 years, compared with a median age of 70 years in the general population.
These findings “highlight the importance” of both screening for stroke risk factors and then starting management steps to minimize these risk factors “immediately and aggressively” after HIV infection is first identified, said Dr. Lin, a researcher at Lin Shin Hospital in Taichung, Taiwan.
Dr. Lin and an associate used data collected by the national health system of Taiwan for about 23 million residents who received care during 1998-2005. They identified 5,961 patients first diagnosed with an HIV infection during this period who had no history of stroke, and 22,307,214 people managed in the health system during the same time with no diagnosed HIV infection and no stroke history. The researchers then followed the stroke incidence among these people through 2011.
Following their HIV diagnosis, those with an infection had 59 ischemic strokes, 29 hemorrhagic strokes, and 15 strokes of undetermined type during an average follow-up of about 8 years. The researchers compared these incidence rates with the general population using standardized incidence ratios (SIR) that adjusted for age, sex, and duration of follow-up. The median age of those diagnosed with an HIV infection was 32 years, while the median age of the 22 million uninfected residents was 34 years.
The SIR analysis showed the excess rate of strokes was particularly significant among HIV-infected patients aged 65 or younger at the time of their infection diagnosis, and was more elevated in women than in men. Among infected men aged younger than 45 years, the SIR for any stroke was more than twice as high as in similarly aged men in the general population, and more than five times as high among infected women compared with similarly aged women in the general population. Among people infected with HIV when they were aged 45-65 years, the SIR for any stroke was 59% higher among men and three times as high among women. Both men and women who were first diagnosed with an HIV infection when they were aged older than 65 years did not have a significantly different SIR for stroke than the general population.
The researchers did not report information on which antiretroviral therapy the HIV-infected patients received or their immune status and how the level of infection control in infected patients related to their stroke rate.
SOURCE: Lin H-L et al. AIDS 2018, Abstract TUPDB0105.
AMSTERDAM – Patients infected with HIV had a roughly doubled rate of stroke compared with the general population, based on analysis of data collected from about 23 million people in Taiwan – including nearly 6,000 with HIV infection.
The combined rate of both ischemic and hemorrhagic stroke was especially elevated during the first 7 years after a diagnosis of HIV positivity, with a nearly 47-fold increased incidence rate during the first year following HIV diagnosis compared with the general age- and sex-adjusted general population, and a nearly fourfold increased rate during years 1-7, both statistically significant differences, Hui-Lin Lin, MD, reported in a poster at the 22nd International AIDS Conference.
Once the period studied reached 8 or more years out from the time of HIV diagnosis, infected patients showed no statistically significant difference in their stroke rate compared with the general population. For the entire follow-up, the stroke rate was 94% higher among HIV-infected patients compared with the general population, a statistically significant difference.
HIV-infected patients who had a stroke also developed it at a much younger age than did the general population. The median age of the infected patients with a stroke was 49 years, compared with a median age of 70 years in the general population.
These findings “highlight the importance” of both screening for stroke risk factors and then starting management steps to minimize these risk factors “immediately and aggressively” after HIV infection is first identified, said Dr. Lin, a researcher at Lin Shin Hospital in Taichung, Taiwan.
Dr. Lin and an associate used data collected by the national health system of Taiwan for about 23 million residents who received care during 1998-2005. They identified 5,961 patients first diagnosed with an HIV infection during this period who had no history of stroke, and 22,307,214 people managed in the health system during the same time with no diagnosed HIV infection and no stroke history. The researchers then followed the stroke incidence among these people through 2011.
Following their HIV diagnosis, those with an infection had 59 ischemic strokes, 29 hemorrhagic strokes, and 15 strokes of undetermined type during an average follow-up of about 8 years. The researchers compared these incidence rates with the general population using standardized incidence ratios (SIR) that adjusted for age, sex, and duration of follow-up. The median age of those diagnosed with an HIV infection was 32 years, while the median age of the 22 million uninfected residents was 34 years.
The SIR analysis showed the excess rate of strokes was particularly significant among HIV-infected patients aged 65 or younger at the time of their infection diagnosis, and was more elevated in women than in men. Among infected men aged younger than 45 years, the SIR for any stroke was more than twice as high as in similarly aged men in the general population, and more than five times as high among infected women compared with similarly aged women in the general population. Among people infected with HIV when they were aged 45-65 years, the SIR for any stroke was 59% higher among men and three times as high among women. Both men and women who were first diagnosed with an HIV infection when they were aged older than 65 years did not have a significantly different SIR for stroke than the general population.
The researchers did not report information on which antiretroviral therapy the HIV-infected patients received or their immune status and how the level of infection control in infected patients related to their stroke rate.
SOURCE: Lin H-L et al. AIDS 2018, Abstract TUPDB0105.
AMSTERDAM – Patients infected with HIV had a roughly doubled rate of stroke compared with the general population, based on analysis of data collected from about 23 million people in Taiwan – including nearly 6,000 with HIV infection.
The combined rate of both ischemic and hemorrhagic stroke was especially elevated during the first 7 years after a diagnosis of HIV positivity, with a nearly 47-fold increased incidence rate during the first year following HIV diagnosis compared with the general age- and sex-adjusted general population, and a nearly fourfold increased rate during years 1-7, both statistically significant differences, Hui-Lin Lin, MD, reported in a poster at the 22nd International AIDS Conference.
Once the period studied reached 8 or more years out from the time of HIV diagnosis, infected patients showed no statistically significant difference in their stroke rate compared with the general population. For the entire follow-up, the stroke rate was 94% higher among HIV-infected patients compared with the general population, a statistically significant difference.
HIV-infected patients who had a stroke also developed it at a much younger age than did the general population. The median age of the infected patients with a stroke was 49 years, compared with a median age of 70 years in the general population.
These findings “highlight the importance” of both screening for stroke risk factors and then starting management steps to minimize these risk factors “immediately and aggressively” after HIV infection is first identified, said Dr. Lin, a researcher at Lin Shin Hospital in Taichung, Taiwan.
Dr. Lin and an associate used data collected by the national health system of Taiwan for about 23 million residents who received care during 1998-2005. They identified 5,961 patients first diagnosed with an HIV infection during this period who had no history of stroke, and 22,307,214 people managed in the health system during the same time with no diagnosed HIV infection and no stroke history. The researchers then followed the stroke incidence among these people through 2011.
Following their HIV diagnosis, those with an infection had 59 ischemic strokes, 29 hemorrhagic strokes, and 15 strokes of undetermined type during an average follow-up of about 8 years. The researchers compared these incidence rates with the general population using standardized incidence ratios (SIR) that adjusted for age, sex, and duration of follow-up. The median age of those diagnosed with an HIV infection was 32 years, while the median age of the 22 million uninfected residents was 34 years.
The SIR analysis showed the excess rate of strokes was particularly significant among HIV-infected patients aged 65 or younger at the time of their infection diagnosis, and was more elevated in women than in men. Among infected men aged younger than 45 years, the SIR for any stroke was more than twice as high as in similarly aged men in the general population, and more than five times as high among infected women compared with similarly aged women in the general population. Among people infected with HIV when they were aged 45-65 years, the SIR for any stroke was 59% higher among men and three times as high among women. Both men and women who were first diagnosed with an HIV infection when they were aged older than 65 years did not have a significantly different SIR for stroke than the general population.
The researchers did not report information on which antiretroviral therapy the HIV-infected patients received or their immune status and how the level of infection control in infected patients related to their stroke rate.
SOURCE: Lin H-L et al. AIDS 2018, Abstract TUPDB0105.
REPORTING FROM AIDS 2018
Key clinical point: Strokes occurred significantly more often in HIV-infected patients than in the general population.
Major finding: The stroke incidence was 94% higher among HIV-infected patients than in the general population.
Study details: A review of health insurance records from about 23 million people in Taiwan during 1998-2011.
Disclosures: Dr. Lin had no disclosures.
Source: Lin H-L et al. AIDS 2018, Abstract TUPDB0105.