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HIV, HBV, and HCV Increase Risks After Joint Replacement
As patients with HIV, hepatitis B (HBV), and hepatitis C (HCV) live longer, more active lives with the help of antiviral treatments, they are now more often having joint replacement surgeries. But HIV, HBV, and HCV can increase the risk of postoperative complications, say researchers from Duke University in North Carolina.
The researchers studied 16,338 patients in 4 cohorts: those with HIV, HBV, HCV, and HIV plus HBV or HCV. They evaluated the patients at 30 days, 90 days, and 2 years after total joint arthroplasty (TJA), comparing their progress with that of a control group.
Patients with HBV and HCV were at risk of both acute and long-term medical and surgical complications. At 90 days and 2 years, the participants had increased risk of pneumonia, sepsis, joint infection, and revision surgery. They also had a greater risk of complications than did patients with HIV, especially for infection, within the first 90 days postsurgery.
Notably, after TJA, patients with HCV had increased risk of acute kidney injury, sepsis, and transfusion at 30 and 90 days. After hip replacement, patients with HBV had a higher risk of acute kidney injury, pneumonia, and transfusion at 30 and 90 days.
Only 364 patients in the study had both HIV and HBV or HBC, but they did have a greater risk of transfusion at 30 and 90 days following both knee and hip surgery.
Following total hip arthroplasty, patients with HIV were more at risk for deep vein thrombosis and transfusion rather than infection. The lower incidence of infection is likely to be related to effective highly active antiretroviral therapy, the researchers say. HIV patients also were more likely to have mechanical complications, such as loosening, periprosthetic fracture, and revision at 90 days, but not at 2 years. Patients with HIV who underwent total knee arthroplasty (TKA) had a higher risk of death at 30 days and medical complications at 90 days. At 2 years, they had a higher risk of periprosthetic joint infection, irrigation and debridement, and revision. The researchers say the higher incidence of mechanical complications can be explained by the younger, more active, and healthy HIV patients in the cohort—the majority were aged younger than 65 years. They also emphasize that the only risk of infection following TJA in their study was 2 years after TKA.
The researchers suggest that their findings could help prompt future guidelines supporting routine screening prior to elective TJA.
Source:
Kildow BJ, Politzer CS, DiLallo M, Bolognesi MP, Seyler TM. J Arthroplasty. 2018;33(suppl 7):S86-S92.
doi: 10.1016/j.arth.2017.10.061.
As patients with HIV, hepatitis B (HBV), and hepatitis C (HCV) live longer, more active lives with the help of antiviral treatments, they are now more often having joint replacement surgeries. But HIV, HBV, and HCV can increase the risk of postoperative complications, say researchers from Duke University in North Carolina.
The researchers studied 16,338 patients in 4 cohorts: those with HIV, HBV, HCV, and HIV plus HBV or HCV. They evaluated the patients at 30 days, 90 days, and 2 years after total joint arthroplasty (TJA), comparing their progress with that of a control group.
Patients with HBV and HCV were at risk of both acute and long-term medical and surgical complications. At 90 days and 2 years, the participants had increased risk of pneumonia, sepsis, joint infection, and revision surgery. They also had a greater risk of complications than did patients with HIV, especially for infection, within the first 90 days postsurgery.
Notably, after TJA, patients with HCV had increased risk of acute kidney injury, sepsis, and transfusion at 30 and 90 days. After hip replacement, patients with HBV had a higher risk of acute kidney injury, pneumonia, and transfusion at 30 and 90 days.
Only 364 patients in the study had both HIV and HBV or HBC, but they did have a greater risk of transfusion at 30 and 90 days following both knee and hip surgery.
Following total hip arthroplasty, patients with HIV were more at risk for deep vein thrombosis and transfusion rather than infection. The lower incidence of infection is likely to be related to effective highly active antiretroviral therapy, the researchers say. HIV patients also were more likely to have mechanical complications, such as loosening, periprosthetic fracture, and revision at 90 days, but not at 2 years. Patients with HIV who underwent total knee arthroplasty (TKA) had a higher risk of death at 30 days and medical complications at 90 days. At 2 years, they had a higher risk of periprosthetic joint infection, irrigation and debridement, and revision. The researchers say the higher incidence of mechanical complications can be explained by the younger, more active, and healthy HIV patients in the cohort—the majority were aged younger than 65 years. They also emphasize that the only risk of infection following TJA in their study was 2 years after TKA.
The researchers suggest that their findings could help prompt future guidelines supporting routine screening prior to elective TJA.
Source:
Kildow BJ, Politzer CS, DiLallo M, Bolognesi MP, Seyler TM. J Arthroplasty. 2018;33(suppl 7):S86-S92.
doi: 10.1016/j.arth.2017.10.061.
As patients with HIV, hepatitis B (HBV), and hepatitis C (HCV) live longer, more active lives with the help of antiviral treatments, they are now more often having joint replacement surgeries. But HIV, HBV, and HCV can increase the risk of postoperative complications, say researchers from Duke University in North Carolina.
The researchers studied 16,338 patients in 4 cohorts: those with HIV, HBV, HCV, and HIV plus HBV or HCV. They evaluated the patients at 30 days, 90 days, and 2 years after total joint arthroplasty (TJA), comparing their progress with that of a control group.
Patients with HBV and HCV were at risk of both acute and long-term medical and surgical complications. At 90 days and 2 years, the participants had increased risk of pneumonia, sepsis, joint infection, and revision surgery. They also had a greater risk of complications than did patients with HIV, especially for infection, within the first 90 days postsurgery.
Notably, after TJA, patients with HCV had increased risk of acute kidney injury, sepsis, and transfusion at 30 and 90 days. After hip replacement, patients with HBV had a higher risk of acute kidney injury, pneumonia, and transfusion at 30 and 90 days.
Only 364 patients in the study had both HIV and HBV or HBC, but they did have a greater risk of transfusion at 30 and 90 days following both knee and hip surgery.
Following total hip arthroplasty, patients with HIV were more at risk for deep vein thrombosis and transfusion rather than infection. The lower incidence of infection is likely to be related to effective highly active antiretroviral therapy, the researchers say. HIV patients also were more likely to have mechanical complications, such as loosening, periprosthetic fracture, and revision at 90 days, but not at 2 years. Patients with HIV who underwent total knee arthroplasty (TKA) had a higher risk of death at 30 days and medical complications at 90 days. At 2 years, they had a higher risk of periprosthetic joint infection, irrigation and debridement, and revision. The researchers say the higher incidence of mechanical complications can be explained by the younger, more active, and healthy HIV patients in the cohort—the majority were aged younger than 65 years. They also emphasize that the only risk of infection following TJA in their study was 2 years after TKA.
The researchers suggest that their findings could help prompt future guidelines supporting routine screening prior to elective TJA.
Source:
Kildow BJ, Politzer CS, DiLallo M, Bolognesi MP, Seyler TM. J Arthroplasty. 2018;33(suppl 7):S86-S92.
doi: 10.1016/j.arth.2017.10.061.
Etravirine Lowers Risk of Hospitalization for Patients With HIV
When all 3 original classes of antiretroviral drugs no longer suppress viral load in a patient with HIV, the next step may be a new drug like etravirine (ETR), a nonnucleoside reverse transcriptase inhibitor (NNRTI). And, according to a French study, that could be a good way of keeping patients out of the hospital.
Using data from the French Hospital Database on HIV (FHDH), researchers analyzed hospitalization rates among heavily treated HIV-1 infected patients on failing regimens between 2005 (etravirine became available in France in 2006) and 2011. They compared 2 groups of patients: those who had received ETR plus a ritonavir-boosted protease inhibitor (PI) and those who had not. The primary endpoint of the study was hospitalization, divided by AIDS-defining cause and non–AIDS-defining cause.
Of 3,884 patients who had been exposed to at least 2 nucleoside reverse transcriptase inhibitors (NRTI), 2 PIs, and 1 NNRTI, 838 received ETR + PI.
During 13,986 person-years of follow-up, there were 2,484 hospitalizations among 956 patients: 617 were from an AIDS-defining cause in 301 patients, and 1,867 from a non–AIDS-defining cause in 828 patients.
The ETR + PI was associated with a 20% reduction in the hospitalization rate, mainly due to the reduction in AIDS hospitalizations. The researchers suggest that the clinical benefit of ETR could be explained by a high rate of virologic suppression (62% at month 6) and excellent tolerability. The FHDH did not include adherence data, but adherence is “unlikely” to explain the better outcome, the researchers say, given that ETR is a twice-daily drug, which may lead to slightly lower adherence than does a once-daily regimen.
The is the first study, to their knowledge, the researchers say, to focus on the risk of hospitalizations in current clinical practice and to show a positive effect.
Source:
Potard V, Goujard C, Valantin MA, et al. BMC Infect Dis. 2018;8:326.
doi: 10.1186/s12879-018-3231-5.
When all 3 original classes of antiretroviral drugs no longer suppress viral load in a patient with HIV, the next step may be a new drug like etravirine (ETR), a nonnucleoside reverse transcriptase inhibitor (NNRTI). And, according to a French study, that could be a good way of keeping patients out of the hospital.
Using data from the French Hospital Database on HIV (FHDH), researchers analyzed hospitalization rates among heavily treated HIV-1 infected patients on failing regimens between 2005 (etravirine became available in France in 2006) and 2011. They compared 2 groups of patients: those who had received ETR plus a ritonavir-boosted protease inhibitor (PI) and those who had not. The primary endpoint of the study was hospitalization, divided by AIDS-defining cause and non–AIDS-defining cause.
Of 3,884 patients who had been exposed to at least 2 nucleoside reverse transcriptase inhibitors (NRTI), 2 PIs, and 1 NNRTI, 838 received ETR + PI.
During 13,986 person-years of follow-up, there were 2,484 hospitalizations among 956 patients: 617 were from an AIDS-defining cause in 301 patients, and 1,867 from a non–AIDS-defining cause in 828 patients.
The ETR + PI was associated with a 20% reduction in the hospitalization rate, mainly due to the reduction in AIDS hospitalizations. The researchers suggest that the clinical benefit of ETR could be explained by a high rate of virologic suppression (62% at month 6) and excellent tolerability. The FHDH did not include adherence data, but adherence is “unlikely” to explain the better outcome, the researchers say, given that ETR is a twice-daily drug, which may lead to slightly lower adherence than does a once-daily regimen.
The is the first study, to their knowledge, the researchers say, to focus on the risk of hospitalizations in current clinical practice and to show a positive effect.
Source:
Potard V, Goujard C, Valantin MA, et al. BMC Infect Dis. 2018;8:326.
doi: 10.1186/s12879-018-3231-5.
When all 3 original classes of antiretroviral drugs no longer suppress viral load in a patient with HIV, the next step may be a new drug like etravirine (ETR), a nonnucleoside reverse transcriptase inhibitor (NNRTI). And, according to a French study, that could be a good way of keeping patients out of the hospital.
Using data from the French Hospital Database on HIV (FHDH), researchers analyzed hospitalization rates among heavily treated HIV-1 infected patients on failing regimens between 2005 (etravirine became available in France in 2006) and 2011. They compared 2 groups of patients: those who had received ETR plus a ritonavir-boosted protease inhibitor (PI) and those who had not. The primary endpoint of the study was hospitalization, divided by AIDS-defining cause and non–AIDS-defining cause.
Of 3,884 patients who had been exposed to at least 2 nucleoside reverse transcriptase inhibitors (NRTI), 2 PIs, and 1 NNRTI, 838 received ETR + PI.
During 13,986 person-years of follow-up, there were 2,484 hospitalizations among 956 patients: 617 were from an AIDS-defining cause in 301 patients, and 1,867 from a non–AIDS-defining cause in 828 patients.
The ETR + PI was associated with a 20% reduction in the hospitalization rate, mainly due to the reduction in AIDS hospitalizations. The researchers suggest that the clinical benefit of ETR could be explained by a high rate of virologic suppression (62% at month 6) and excellent tolerability. The FHDH did not include adherence data, but adherence is “unlikely” to explain the better outcome, the researchers say, given that ETR is a twice-daily drug, which may lead to slightly lower adherence than does a once-daily regimen.
The is the first study, to their knowledge, the researchers say, to focus on the risk of hospitalizations in current clinical practice and to show a positive effect.
Source:
Potard V, Goujard C, Valantin MA, et al. BMC Infect Dis. 2018;8:326.
doi: 10.1186/s12879-018-3231-5.
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
Ibalizumab shows promise against MDR HIV-1
In combination with an optimized background regimen, the humanized IgG4 monoclonal antibody ibalizumab can reduce viral load and increase CD4 counts in patients with multidrug-resistant HIV type 1 (MDR HIV-1), according to a study published in the New England Journal of Medicine. It does so by binding noncompetitively to CD4 receptors, which can thereby block HIV-1 entry.
TMB-301 (NCT02475629) was a 24-week, open-label, single-group, phase 3 study that included patients with MDR HIV-1. During July 2015 to October 2016, patients first continued on their previous treatment for 7 days, then were given a 2,000-mg loading dose of ibalizumab as monotherapy, and then continued on 800 mg ibalizumab every 14 days plus an individualized regimen that was optimized based on patients’ past treatments for the remainder of the study period.
The primary endpoint was how many patients experienced a decrease in viral load of at least 0.5 log10 copies/mL from baseline to day 14 – that is, after the 7-day control period plus the 7-days ibalizumab monotherapy period. This occurred in 33 of the 40 patients (83%; 95% confidence interval, 67%-93%; P less than .001); in fact, 60% of patients (n = 24) experienced a decrease of at least 1.0 log10 copies/mL during that period, and the mean and median reductions were 1.1 log10 copies/mL. One secondary end point was increase in CD4 counts: The mean increase was 62 cells/mcL, although smaller increases were seen among patients with lower starting counts. Of the 10 patients who exhibited virologic failure or rebound, 9 showed less susceptibility to ibalizumab at week 25 than they had shown at baseline.
At least one adverse event was seen in 32 patients (80%), although most (87%) of those events were mild to moderate in severity, such as diarrhea (20%) and nausea, fatigue, pyrexia, rash, and dizziness (13% each). More serious events (grade 3 or 4) were seen in 28% of patients (n = 11); serious events were seen in nine patients – including immune reconstitution inflammatory syndrome in one. Four patients died during the study, although none of the deaths were believed to have been related to treatment with ibalizumab.
The investigators noted that the study’s limitations – its small size, uncontrolled design, and limited time for analyzing secondary and safety endpoints – were largely related to small number of patients with MDR HIV-1. The investigators noted that, in accordance with HIV treatment guidelines, patients who experience resistance-related treatment failure should be started on a regimen that includes at least two fully active agents; the investigators suggest that the addition of a drug like ibalizumab provides new opportunities for effective treatments in these situations.
This study was originally presented at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.
The study was supported by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed, which developed ibalizumab. The authors disclosed ties to various industry entities, including grants, personal fees, nonfinancial support, and other forms of support from TaiMed.
SOURCE: Emu B et al. New Engl J Med. 2018 Aug 16;379(9):645-54.
In combination with an optimized background regimen, the humanized IgG4 monoclonal antibody ibalizumab can reduce viral load and increase CD4 counts in patients with multidrug-resistant HIV type 1 (MDR HIV-1), according to a study published in the New England Journal of Medicine. It does so by binding noncompetitively to CD4 receptors, which can thereby block HIV-1 entry.
TMB-301 (NCT02475629) was a 24-week, open-label, single-group, phase 3 study that included patients with MDR HIV-1. During July 2015 to October 2016, patients first continued on their previous treatment for 7 days, then were given a 2,000-mg loading dose of ibalizumab as monotherapy, and then continued on 800 mg ibalizumab every 14 days plus an individualized regimen that was optimized based on patients’ past treatments for the remainder of the study period.
The primary endpoint was how many patients experienced a decrease in viral load of at least 0.5 log10 copies/mL from baseline to day 14 – that is, after the 7-day control period plus the 7-days ibalizumab monotherapy period. This occurred in 33 of the 40 patients (83%; 95% confidence interval, 67%-93%; P less than .001); in fact, 60% of patients (n = 24) experienced a decrease of at least 1.0 log10 copies/mL during that period, and the mean and median reductions were 1.1 log10 copies/mL. One secondary end point was increase in CD4 counts: The mean increase was 62 cells/mcL, although smaller increases were seen among patients with lower starting counts. Of the 10 patients who exhibited virologic failure or rebound, 9 showed less susceptibility to ibalizumab at week 25 than they had shown at baseline.
At least one adverse event was seen in 32 patients (80%), although most (87%) of those events were mild to moderate in severity, such as diarrhea (20%) and nausea, fatigue, pyrexia, rash, and dizziness (13% each). More serious events (grade 3 or 4) were seen in 28% of patients (n = 11); serious events were seen in nine patients – including immune reconstitution inflammatory syndrome in one. Four patients died during the study, although none of the deaths were believed to have been related to treatment with ibalizumab.
The investigators noted that the study’s limitations – its small size, uncontrolled design, and limited time for analyzing secondary and safety endpoints – were largely related to small number of patients with MDR HIV-1. The investigators noted that, in accordance with HIV treatment guidelines, patients who experience resistance-related treatment failure should be started on a regimen that includes at least two fully active agents; the investigators suggest that the addition of a drug like ibalizumab provides new opportunities for effective treatments in these situations.
This study was originally presented at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.
The study was supported by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed, which developed ibalizumab. The authors disclosed ties to various industry entities, including grants, personal fees, nonfinancial support, and other forms of support from TaiMed.
SOURCE: Emu B et al. New Engl J Med. 2018 Aug 16;379(9):645-54.
In combination with an optimized background regimen, the humanized IgG4 monoclonal antibody ibalizumab can reduce viral load and increase CD4 counts in patients with multidrug-resistant HIV type 1 (MDR HIV-1), according to a study published in the New England Journal of Medicine. It does so by binding noncompetitively to CD4 receptors, which can thereby block HIV-1 entry.
TMB-301 (NCT02475629) was a 24-week, open-label, single-group, phase 3 study that included patients with MDR HIV-1. During July 2015 to October 2016, patients first continued on their previous treatment for 7 days, then were given a 2,000-mg loading dose of ibalizumab as monotherapy, and then continued on 800 mg ibalizumab every 14 days plus an individualized regimen that was optimized based on patients’ past treatments for the remainder of the study period.
The primary endpoint was how many patients experienced a decrease in viral load of at least 0.5 log10 copies/mL from baseline to day 14 – that is, after the 7-day control period plus the 7-days ibalizumab monotherapy period. This occurred in 33 of the 40 patients (83%; 95% confidence interval, 67%-93%; P less than .001); in fact, 60% of patients (n = 24) experienced a decrease of at least 1.0 log10 copies/mL during that period, and the mean and median reductions were 1.1 log10 copies/mL. One secondary end point was increase in CD4 counts: The mean increase was 62 cells/mcL, although smaller increases were seen among patients with lower starting counts. Of the 10 patients who exhibited virologic failure or rebound, 9 showed less susceptibility to ibalizumab at week 25 than they had shown at baseline.
At least one adverse event was seen in 32 patients (80%), although most (87%) of those events were mild to moderate in severity, such as diarrhea (20%) and nausea, fatigue, pyrexia, rash, and dizziness (13% each). More serious events (grade 3 or 4) were seen in 28% of patients (n = 11); serious events were seen in nine patients – including immune reconstitution inflammatory syndrome in one. Four patients died during the study, although none of the deaths were believed to have been related to treatment with ibalizumab.
The investigators noted that the study’s limitations – its small size, uncontrolled design, and limited time for analyzing secondary and safety endpoints – were largely related to small number of patients with MDR HIV-1. The investigators noted that, in accordance with HIV treatment guidelines, patients who experience resistance-related treatment failure should be started on a regimen that includes at least two fully active agents; the investigators suggest that the addition of a drug like ibalizumab provides new opportunities for effective treatments in these situations.
This study was originally presented at the Conference on Retroviruses & Opportunistic Infections in partnership with the International Antiviral Society.
The study was supported by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed, which developed ibalizumab. The authors disclosed ties to various industry entities, including grants, personal fees, nonfinancial support, and other forms of support from TaiMed.
SOURCE: Emu B et al. New Engl J Med. 2018 Aug 16;379(9):645-54.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
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.
Genetic composition of HCV changes with HIV coinfection
Marked differences were seen in the composition of hepatitis C virus hypervariable region 1 (HVR1) when comparing HIV-coinfected (CIP) with HCV-monoinfected (MIP) individuals, according to the results of a genetic analysis of nearly 300 patients.
Intrahost HCV HVR1 evolution varies between these two groups, which suggests that HIV-inflicted changes in the host environment exact a strong HCV genetic response, according to a report published online in Infection, Genetics, and Evolution.
“A high prevalence of HIV-HCV coinfection and its impact on mortality among such populations groups as PWID [people who inject drugs] and MSM [men who have sex with men] is of major concern to public health,” according to the researchers.
Previous studies using the Global Hepatitis Outbreak and Surveillance Technology, a Web-based system for the detection of HCV transmission developed by the researchers, analyzed sequences of intrahost variants of the HVR1 region using next-generation sequencing. They found that genetic variation in the HVR1 of intrahost HCV variants was strongly associated with host sex and ethnicity, resistance to interferon, and stages of HCV infection.
In this particular study, the researchers assessed 28,622 nucleotide sequences of intrahost HCV HVR1 variants from 113 CIP and 176 MIP individuals.
They examined 148 physical-chemical indexes of DNA nucleotide dimers and found that there were significant differences in the means and frequency distributions of seven physical-chemical properties between HVR1 variants from both groups.
The significant majority of these profiles (98%-99%) were found to be specific to CIP or MIP, indicating that coevolution among HVR1 sites reflects HCV adaptation to HIV among coinfected individuals. “This observation suggests substantial differences in fitness between HVR1 variants circulating in infected hosts in the presence or absence of HIV, according to the researchers from the Centers for Disease Control and Prevention.
“HCV strains circulating in high-risk groups need to be carefully monitored for the identification of potentially new traits of clinical and public health relevance,” the researchers concluded.
This study was supported by CDC intramural funding. The authors reported that they had no disclosures.
SOURCE: Lara J et al. doi: 10.1016/j.meegid.2018.07.039.
Marked differences were seen in the composition of hepatitis C virus hypervariable region 1 (HVR1) when comparing HIV-coinfected (CIP) with HCV-monoinfected (MIP) individuals, according to the results of a genetic analysis of nearly 300 patients.
Intrahost HCV HVR1 evolution varies between these two groups, which suggests that HIV-inflicted changes in the host environment exact a strong HCV genetic response, according to a report published online in Infection, Genetics, and Evolution.
“A high prevalence of HIV-HCV coinfection and its impact on mortality among such populations groups as PWID [people who inject drugs] and MSM [men who have sex with men] is of major concern to public health,” according to the researchers.
Previous studies using the Global Hepatitis Outbreak and Surveillance Technology, a Web-based system for the detection of HCV transmission developed by the researchers, analyzed sequences of intrahost variants of the HVR1 region using next-generation sequencing. They found that genetic variation in the HVR1 of intrahost HCV variants was strongly associated with host sex and ethnicity, resistance to interferon, and stages of HCV infection.
In this particular study, the researchers assessed 28,622 nucleotide sequences of intrahost HCV HVR1 variants from 113 CIP and 176 MIP individuals.
They examined 148 physical-chemical indexes of DNA nucleotide dimers and found that there were significant differences in the means and frequency distributions of seven physical-chemical properties between HVR1 variants from both groups.
The significant majority of these profiles (98%-99%) were found to be specific to CIP or MIP, indicating that coevolution among HVR1 sites reflects HCV adaptation to HIV among coinfected individuals. “This observation suggests substantial differences in fitness between HVR1 variants circulating in infected hosts in the presence or absence of HIV, according to the researchers from the Centers for Disease Control and Prevention.
“HCV strains circulating in high-risk groups need to be carefully monitored for the identification of potentially new traits of clinical and public health relevance,” the researchers concluded.
This study was supported by CDC intramural funding. The authors reported that they had no disclosures.
SOURCE: Lara J et al. doi: 10.1016/j.meegid.2018.07.039.
Marked differences were seen in the composition of hepatitis C virus hypervariable region 1 (HVR1) when comparing HIV-coinfected (CIP) with HCV-monoinfected (MIP) individuals, according to the results of a genetic analysis of nearly 300 patients.
Intrahost HCV HVR1 evolution varies between these two groups, which suggests that HIV-inflicted changes in the host environment exact a strong HCV genetic response, according to a report published online in Infection, Genetics, and Evolution.
“A high prevalence of HIV-HCV coinfection and its impact on mortality among such populations groups as PWID [people who inject drugs] and MSM [men who have sex with men] is of major concern to public health,” according to the researchers.
Previous studies using the Global Hepatitis Outbreak and Surveillance Technology, a Web-based system for the detection of HCV transmission developed by the researchers, analyzed sequences of intrahost variants of the HVR1 region using next-generation sequencing. They found that genetic variation in the HVR1 of intrahost HCV variants was strongly associated with host sex and ethnicity, resistance to interferon, and stages of HCV infection.
In this particular study, the researchers assessed 28,622 nucleotide sequences of intrahost HCV HVR1 variants from 113 CIP and 176 MIP individuals.
They examined 148 physical-chemical indexes of DNA nucleotide dimers and found that there were significant differences in the means and frequency distributions of seven physical-chemical properties between HVR1 variants from both groups.
The significant majority of these profiles (98%-99%) were found to be specific to CIP or MIP, indicating that coevolution among HVR1 sites reflects HCV adaptation to HIV among coinfected individuals. “This observation suggests substantial differences in fitness between HVR1 variants circulating in infected hosts in the presence or absence of HIV, according to the researchers from the Centers for Disease Control and Prevention.
“HCV strains circulating in high-risk groups need to be carefully monitored for the identification of potentially new traits of clinical and public health relevance,” the researchers concluded.
This study was supported by CDC intramural funding. The authors reported that they had no disclosures.
SOURCE: Lara J et al. doi: 10.1016/j.meegid.2018.07.039.
FROM INFECTION, GENETICS, AND EVOLUTION