Susan London

SEATTLE – HIV-positive patients are increasingly initiating antiretroviral treatment early in the course of their disease, which should improve their outcomes, suggests a study conducted in San Francisco.

However, some groups are clearly not included in this favorable trend, said the study’s lead investigator, Hong-Ha M. Truong, Ph.D., an assistant professor of medicine at the University of California, San Francisco.

Overall, the findings reflect the implementation of a test-and-treat approach recently introduced in San Francisco aimed at increasing early use of antiretroviral therapy (ART) among HIV-positives and reducing CD4 cell loss in the interval between HIV diagnosis and treatment initiation, said Kholoud Porter, Ph.D., session comoderator and senior epidemiologist with the Medical Research Council (MRC) Clinical Trials Unit in London.

"Given the need for good adherence to lifelong ART, it will be crucial to monitor these individuals and document the proportion who remain on ART and maintain viral suppression," she said at the Conference on Retroviruses and Opportunistic Infections.

The disparity in early ART uptake should inform public health policy, she added.

The study involved more than 3,750 adolescents and adults from the city’s HIV/AIDS Case Registry; their infections were diagnosed between 2004 and 2010.

Dr. Truong and her colleagues showed that the proportion of patients initiating ART early, that is, at a CD4 count of greater than 350 cells/mm³, increased dramatically: Among those who had a count above this value at diagnosis and initiated ART during the study period, only about half (48%) initiated early in 2004, whereas nearly all (93%) did so in 2010, she reported.

In adjusted analyses, however, the proportion of patients initiating ART early was significantly lower among racial/ethnic minorities, young individuals, injection drug users, patients whose diagnosis was made in nonprivate facilities, and those living in impoverished areas.

"Early initiation of ART at high CD4 levels was evident in San Francisco starting as early as 2007," said Dr. Truong, noting that this trend predated changes to local treatment recommendations calling for initiation regardless of CD4 count. "However, not all groups are accessing early initiation of ART equally, and therefore [they are] not benefiting from the advantages of early treatment."

"Delays in treatment initiation explain observed disparities in survival among persons living with HIV. Disparities will persist unless treatment gaps are closed," she maintained.

There may be financial barriers to accessing antiretrovirals, she said. Insurance companies may require CD4 counts of a certain level before they will cover antiretrovirals. But more likely, individuals and their motivation to seek treatment are driving this trend, she said. San Francisco also has a countywide health care program that provides access to people who don’t have health insurance.

For the study, the investigators identified 3,778 San Francisco HIV-positive patients aged 13 years or older. Results were largely based on 1,803 having a CD4 count of greater than 350 cells/mm³ at diagnosis, and specifically the 941 who initiated ART.

National guidelines at the start of the study period in 2004 recommended that HIV-positive patients begin ART when their CD4 count dropped below 350 cells/mm³, Dr. Truong noted. (They have since been updated to recommend initiation at 500 cells/mm³ or less, with initiation at higher levels optional.)

"Recognizing the beneficial impact of early treatment on reducing morbidity and transmission, public health clinics and the Positive Health Program in San Francisco revised their guidelines in 2010," Dr. Truong explained. "The new recommendations called for initiating treatment at the time of HIV diagnosis, irrespective of CD4 counts."

The median count at diagnosis remained essentially stable during the 7-year study period, at roughly 550 cells/mm³, whereas that at ART initiation increased, from 365 to 496 cells/mm³ (P less than .001). Thus, the gap between the two values narrowed (P less than .001).

Dr. Truong and Dr. Porter reported having no relevant conflicts of interest.

SEATTLE – HIV-positive patients are increasingly initiating antiretroviral treatment early in the course of their disease, which should improve their outcomes, suggests a study conducted in San Francisco.

However, some groups are clearly not included in this favorable trend, said the study’s lead investigator, Hong-Ha M. Truong, Ph.D., an assistant professor of medicine at the University of California, San Francisco.

Overall, the findings reflect the implementation of a test-and-treat approach recently introduced in San Francisco aimed at increasing early use of antiretroviral therapy (ART) among HIV-positives and reducing CD4 cell loss in the interval between HIV diagnosis and treatment initiation, said Kholoud Porter, Ph.D., session comoderator and senior epidemiologist with the Medical Research Council (MRC) Clinical Trials Unit in London.

"Given the need for good adherence to lifelong ART, it will be crucial to monitor these individuals and document the proportion who remain on ART and maintain viral suppression," she said at the Conference on Retroviruses and Opportunistic Infections.

The disparity in early ART uptake should inform public health policy, she added.

The study involved more than 3,750 adolescents and adults from the city’s HIV/AIDS Case Registry; their infections were diagnosed between 2004 and 2010.

Dr. Truong and her colleagues showed that the proportion of patients initiating ART early, that is, at a CD4 count of greater than 350 cells/mm³, increased dramatically: Among those who had a count above this value at diagnosis and initiated ART during the study period, only about half (48%) initiated early in 2004, whereas nearly all (93%) did so in 2010, she reported.

In adjusted analyses, however, the proportion of patients initiating ART early was significantly lower among racial/ethnic minorities, young individuals, injection drug users, patients whose diagnosis was made in nonprivate facilities, and those living in impoverished areas.

"Early initiation of ART at high CD4 levels was evident in San Francisco starting as early as 2007," said Dr. Truong, noting that this trend predated changes to local treatment recommendations calling for initiation regardless of CD4 count. "However, not all groups are accessing early initiation of ART equally, and therefore [they are] not benefiting from the advantages of early treatment."

"Delays in treatment initiation explain observed disparities in survival among persons living with HIV. Disparities will persist unless treatment gaps are closed," she maintained.

There may be financial barriers to accessing antiretrovirals, she said. Insurance companies may require CD4 counts of a certain level before they will cover antiretrovirals. But more likely, individuals and their motivation to seek treatment are driving this trend, she said. San Francisco also has a countywide health care program that provides access to people who don’t have health insurance.

For the study, the investigators identified 3,778 San Francisco HIV-positive patients aged 13 years or older. Results were largely based on 1,803 having a CD4 count of greater than 350 cells/mm³ at diagnosis, and specifically the 941 who initiated ART.

National guidelines at the start of the study period in 2004 recommended that HIV-positive patients begin ART when their CD4 count dropped below 350 cells/mm³, Dr. Truong noted. (They have since been updated to recommend initiation at 500 cells/mm³ or less, with initiation at higher levels optional.)

"Recognizing the beneficial impact of early treatment on reducing morbidity and transmission, public health clinics and the Positive Health Program in San Francisco revised their guidelines in 2010," Dr. Truong explained. "The new recommendations called for initiating treatment at the time of HIV diagnosis, irrespective of CD4 counts."

The median count at diagnosis remained essentially stable during the 7-year study period, at roughly 550 cells/mm³, whereas that at ART initiation increased, from 365 to 496 cells/mm³ (P less than .001). Thus, the gap between the two values narrowed (P less than .001).

Dr. Truong and Dr. Porter reported having no relevant conflicts of interest.

SEATTLE – HIV-positive patients are increasingly initiating antiretroviral treatment early in the course of their disease, which should improve their outcomes, suggests a study conducted in San Francisco.

However, some groups are clearly not included in this favorable trend, said the study’s lead investigator, Hong-Ha M. Truong, Ph.D., an assistant professor of medicine at the University of California, San Francisco.

Overall, the findings reflect the implementation of a test-and-treat approach recently introduced in San Francisco aimed at increasing early use of antiretroviral therapy (ART) among HIV-positives and reducing CD4 cell loss in the interval between HIV diagnosis and treatment initiation, said Kholoud Porter, Ph.D., session comoderator and senior epidemiologist with the Medical Research Council (MRC) Clinical Trials Unit in London.

"Given the need for good adherence to lifelong ART, it will be crucial to monitor these individuals and document the proportion who remain on ART and maintain viral suppression," she said at the Conference on Retroviruses and Opportunistic Infections.

The disparity in early ART uptake should inform public health policy, she added.

The study involved more than 3,750 adolescents and adults from the city’s HIV/AIDS Case Registry; their infections were diagnosed between 2004 and 2010.

Dr. Truong and her colleagues showed that the proportion of patients initiating ART early, that is, at a CD4 count of greater than 350 cells/mm³, increased dramatically: Among those who had a count above this value at diagnosis and initiated ART during the study period, only about half (48%) initiated early in 2004, whereas nearly all (93%) did so in 2010, she reported.

In adjusted analyses, however, the proportion of patients initiating ART early was significantly lower among racial/ethnic minorities, young individuals, injection drug users, patients whose diagnosis was made in nonprivate facilities, and those living in impoverished areas.

"Early initiation of ART at high CD4 levels was evident in San Francisco starting as early as 2007," said Dr. Truong, noting that this trend predated changes to local treatment recommendations calling for initiation regardless of CD4 count. "However, not all groups are accessing early initiation of ART equally, and therefore [they are] not benefiting from the advantages of early treatment."

"Delays in treatment initiation explain observed disparities in survival among persons living with HIV. Disparities will persist unless treatment gaps are closed," she maintained.

There may be financial barriers to accessing antiretrovirals, she said. Insurance companies may require CD4 counts of a certain level before they will cover antiretrovirals. But more likely, individuals and their motivation to seek treatment are driving this trend, she said. San Francisco also has a countywide health care program that provides access to people who don’t have health insurance.

For the study, the investigators identified 3,778 San Francisco HIV-positive patients aged 13 years or older. Results were largely based on 1,803 having a CD4 count of greater than 350 cells/mm³ at diagnosis, and specifically the 941 who initiated ART.

National guidelines at the start of the study period in 2004 recommended that HIV-positive patients begin ART when their CD4 count dropped below 350 cells/mm³, Dr. Truong noted. (They have since been updated to recommend initiation at 500 cells/mm³ or less, with initiation at higher levels optional.)

"Recognizing the beneficial impact of early treatment on reducing morbidity and transmission, public health clinics and the Positive Health Program in San Francisco revised their guidelines in 2010," Dr. Truong explained. "The new recommendations called for initiating treatment at the time of HIV diagnosis, irrespective of CD4 counts."

The median count at diagnosis remained essentially stable during the 7-year study period, at roughly 550 cells/mm³, whereas that at ART initiation increased, from 365 to 496 cells/mm³ (P less than .001). Thus, the gap between the two values narrowed (P less than .001).

Dr. Truong and Dr. Porter reported having no relevant conflicts of interest.

SEATTLE – Almost half of patients with newly diagnosed HIV infection appeared to have impaired neuropsychological functioning, according to the findings of a prospective longitudinal study involving 70 men. Initiation of antiretroviral therapy halted this decline but did not reverse it.

Before starting antiretroviral therapy (ART), study patients, who were an average of 4 months into their infection, had declines over time in the motor neuropsychological domain and a composite measure of motor function and processing speed, Dr. Julia Peterson of the University of California, San Francisco, reported at the Conference on Retroviruses and Opportunistic Infections.

Nearly half of patients started ART during follow-up, and after doing so, these patients had stabilization – but not improvement – in both measures.

"These findings suggest that while performance in certain neuropsychological domains may improve with repeated testing, a decline in motor performance is measurable in patients with untreated HIV infection, and that this decline may be attenuated with early antiretroviral treatment," Dr. Peterson commented.

"Although it is difficult to discern the reason for the negative trajectory of the motor performance initially in primary HIV infection," an imaging study has shown "accumulating inflammation in the frontal white matter during the same period of time, so this may correspond to the motor dysfunction that we are seeing," she said. Furthermore, as suggested by other research, "there is detection of neuropathy in this same primary infection cohort, which may also lead to motor dysfunction."

When asked whether there might have been a confounding effect of patients’ psychological reaction to such a serious new diagnosis, she acknowledged that was possible, especially at the first study visit.

"I don’t know the perfect way to factor in every single thing that might be affecting the patient at that visit: It could be drug use, it could be anxiety, it could be depression, it could be another diagnosis," she said. However, neuropsychological performance at baseline did not correlate with mental health symptoms.

"Lymphocytic meningitis is common in this setting within the first few months of seroconversion," noted Dr. Rodger MacArthur of Wayne State University in Detroit, who attended the session. "So how did you adjust or correct for that, for individuals who had either symptomatic meningitis or silent meningitis?"

Only a few patients in the cohort were found to have meningitis, and they were excluded from longitudinal analyses, Dr. Peterson said.

Explaining the study’s rationale, she noted, "There are many reports on the persistence of mild neurological and cognitive impairment in patients with chronic HIV infection who are on suppressive treatment. Yet there is limited study on the neuropsychological testing performance early during infection."

The investigators evaluated patients repeatedly over time with 11 neuropsychological tests assessing performance in five domains. They also used two composite measures: the total Z score (reflecting all 11 tests) and the NPZ4 score (reflecting four tests of motor and processing speed). The latter is "more relevant in the clinical setting," Dr. Peterson noted.

The enrolled patients had a median age of 36 years and a median of 16 years of education, and 79% had a history of drug use. On average, they were 125 days post HIV exposure and had a CD4 count of 555 cells/mm³.

At baseline, 42% of the patients performed more than one standard deviation below the normative mean in at least two neuropsychological domains, meeting criteria for asymptomatic neurocognitive impairment or mild neurocognitive disorder.

Longitudinal analyses showed that before starting ART, the patients had declines over time in the motor domain (P = .012) and the NPZ4 composite measure (P = .027).

Forty-seven percent of the patients started ART during follow-up, a median of about 32 weeks after HIV exposure and at a median CD4 count of 433 cells/mm³.

After starting ART, these patients had stabilization in the motor domain (P = NS) and NPZ4 measure (P = NS). They also had new improvement in the executive function domain (P = .001).

"At any point when treatment is initiated, motor performance stabilizes to practically no change and no improvement, thus suggesting ... each patient will maintain any sort of accumulated impairment," commented Dr. Peterson.

Performance in the remaining domain studied, memory, did not change significantly, either before or after ART initiation.

"Treatment was not randomized," she acknowledged. Also, "there was no well-matched control group, so we had to rely on published norms, which may or may not be congruent with our own study population. It is not clear whether baseline or accrued impairment reflects premorbid factors or is actually the effect of HIV."

Dr. Peterson disclosed no relevant conflicts of interest.

SEATTLE – Almost half of patients with newly diagnosed HIV infection appeared to have impaired neuropsychological functioning, according to the findings of a prospective longitudinal study involving 70 men. Initiation of antiretroviral therapy halted this decline but did not reverse it.

Before starting antiretroviral therapy (ART), study patients, who were an average of 4 months into their infection, had declines over time in the motor neuropsychological domain and a composite measure of motor function and processing speed, Dr. Julia Peterson of the University of California, San Francisco, reported at the Conference on Retroviruses and Opportunistic Infections.

Nearly half of patients started ART during follow-up, and after doing so, these patients had stabilization – but not improvement – in both measures.

"These findings suggest that while performance in certain neuropsychological domains may improve with repeated testing, a decline in motor performance is measurable in patients with untreated HIV infection, and that this decline may be attenuated with early antiretroviral treatment," Dr. Peterson commented.

"Although it is difficult to discern the reason for the negative trajectory of the motor performance initially in primary HIV infection," an imaging study has shown "accumulating inflammation in the frontal white matter during the same period of time, so this may correspond to the motor dysfunction that we are seeing," she said. Furthermore, as suggested by other research, "there is detection of neuropathy in this same primary infection cohort, which may also lead to motor dysfunction."

When asked whether there might have been a confounding effect of patients’ psychological reaction to such a serious new diagnosis, she acknowledged that was possible, especially at the first study visit.

"I don’t know the perfect way to factor in every single thing that might be affecting the patient at that visit: It could be drug use, it could be anxiety, it could be depression, it could be another diagnosis," she said. However, neuropsychological performance at baseline did not correlate with mental health symptoms.

"Lymphocytic meningitis is common in this setting within the first few months of seroconversion," noted Dr. Rodger MacArthur of Wayne State University in Detroit, who attended the session. "So how did you adjust or correct for that, for individuals who had either symptomatic meningitis or silent meningitis?"

Only a few patients in the cohort were found to have meningitis, and they were excluded from longitudinal analyses, Dr. Peterson said.

Explaining the study’s rationale, she noted, "There are many reports on the persistence of mild neurological and cognitive impairment in patients with chronic HIV infection who are on suppressive treatment. Yet there is limited study on the neuropsychological testing performance early during infection."

The investigators evaluated patients repeatedly over time with 11 neuropsychological tests assessing performance in five domains. They also used two composite measures: the total Z score (reflecting all 11 tests) and the NPZ4 score (reflecting four tests of motor and processing speed). The latter is "more relevant in the clinical setting," Dr. Peterson noted.

The enrolled patients had a median age of 36 years and a median of 16 years of education, and 79% had a history of drug use. On average, they were 125 days post HIV exposure and had a CD4 count of 555 cells/mm³.

At baseline, 42% of the patients performed more than one standard deviation below the normative mean in at least two neuropsychological domains, meeting criteria for asymptomatic neurocognitive impairment or mild neurocognitive disorder.

Longitudinal analyses showed that before starting ART, the patients had declines over time in the motor domain (P = .012) and the NPZ4 composite measure (P = .027).

Forty-seven percent of the patients started ART during follow-up, a median of about 32 weeks after HIV exposure and at a median CD4 count of 433 cells/mm³.

After starting ART, these patients had stabilization in the motor domain (P = NS) and NPZ4 measure (P = NS). They also had new improvement in the executive function domain (P = .001).

"At any point when treatment is initiated, motor performance stabilizes to practically no change and no improvement, thus suggesting ... each patient will maintain any sort of accumulated impairment," commented Dr. Peterson.

Performance in the remaining domain studied, memory, did not change significantly, either before or after ART initiation.

"Treatment was not randomized," she acknowledged. Also, "there was no well-matched control group, so we had to rely on published norms, which may or may not be congruent with our own study population. It is not clear whether baseline or accrued impairment reflects premorbid factors or is actually the effect of HIV."

Dr. Peterson disclosed no relevant conflicts of interest.

SEATTLE – Almost half of patients with newly diagnosed HIV infection appeared to have impaired neuropsychological functioning, according to the findings of a prospective longitudinal study involving 70 men. Initiation of antiretroviral therapy halted this decline but did not reverse it.

Before starting antiretroviral therapy (ART), study patients, who were an average of 4 months into their infection, had declines over time in the motor neuropsychological domain and a composite measure of motor function and processing speed, Dr. Julia Peterson of the University of California, San Francisco, reported at the Conference on Retroviruses and Opportunistic Infections.

Nearly half of patients started ART during follow-up, and after doing so, these patients had stabilization – but not improvement – in both measures.

"These findings suggest that while performance in certain neuropsychological domains may improve with repeated testing, a decline in motor performance is measurable in patients with untreated HIV infection, and that this decline may be attenuated with early antiretroviral treatment," Dr. Peterson commented.

"Although it is difficult to discern the reason for the negative trajectory of the motor performance initially in primary HIV infection," an imaging study has shown "accumulating inflammation in the frontal white matter during the same period of time, so this may correspond to the motor dysfunction that we are seeing," she said. Furthermore, as suggested by other research, "there is detection of neuropathy in this same primary infection cohort, which may also lead to motor dysfunction."

When asked whether there might have been a confounding effect of patients’ psychological reaction to such a serious new diagnosis, she acknowledged that was possible, especially at the first study visit.

"I don’t know the perfect way to factor in every single thing that might be affecting the patient at that visit: It could be drug use, it could be anxiety, it could be depression, it could be another diagnosis," she said. However, neuropsychological performance at baseline did not correlate with mental health symptoms.

"Lymphocytic meningitis is common in this setting within the first few months of seroconversion," noted Dr. Rodger MacArthur of Wayne State University in Detroit, who attended the session. "So how did you adjust or correct for that, for individuals who had either symptomatic meningitis or silent meningitis?"

Only a few patients in the cohort were found to have meningitis, and they were excluded from longitudinal analyses, Dr. Peterson said.

Explaining the study’s rationale, she noted, "There are many reports on the persistence of mild neurological and cognitive impairment in patients with chronic HIV infection who are on suppressive treatment. Yet there is limited study on the neuropsychological testing performance early during infection."

The investigators evaluated patients repeatedly over time with 11 neuropsychological tests assessing performance in five domains. They also used two composite measures: the total Z score (reflecting all 11 tests) and the NPZ4 score (reflecting four tests of motor and processing speed). The latter is "more relevant in the clinical setting," Dr. Peterson noted.

The enrolled patients had a median age of 36 years and a median of 16 years of education, and 79% had a history of drug use. On average, they were 125 days post HIV exposure and had a CD4 count of 555 cells/mm³.

At baseline, 42% of the patients performed more than one standard deviation below the normative mean in at least two neuropsychological domains, meeting criteria for asymptomatic neurocognitive impairment or mild neurocognitive disorder.

Longitudinal analyses showed that before starting ART, the patients had declines over time in the motor domain (P = .012) and the NPZ4 composite measure (P = .027).

Forty-seven percent of the patients started ART during follow-up, a median of about 32 weeks after HIV exposure and at a median CD4 count of 433 cells/mm³.

After starting ART, these patients had stabilization in the motor domain (P = NS) and NPZ4 measure (P = NS). They also had new improvement in the executive function domain (P = .001).

"At any point when treatment is initiated, motor performance stabilizes to practically no change and no improvement, thus suggesting ... each patient will maintain any sort of accumulated impairment," commented Dr. Peterson.

Performance in the remaining domain studied, memory, did not change significantly, either before or after ART initiation.

"Treatment was not randomized," she acknowledged. Also, "there was no well-matched control group, so we had to rely on published norms, which may or may not be congruent with our own study population. It is not clear whether baseline or accrued impairment reflects premorbid factors or is actually the effect of HIV."

Dr. Peterson disclosed no relevant conflicts of interest.

SEATTLE – HIV-infected individuals have increased arterial inflammation compared with their uninfected counterparts with the same levels of traditional cardiovascular risk factors, even when the infection is so well controlled that the virus is undetectable.

This was among the key findings of an observational study of 81 individuals who underwent fluorodeoxyglucose positron emission tomography (FDG-PET). Inflammation in the thoracic aorta was assessed from the target-to-background ratio of tracer uptake.

Courtesy Dr. Tom Folks, NIAID/National Institutes of Health

Study results, reported at the Conference on Retroviruses and Opportunistic Infections, showed that inflammation in the HIV-positive individuals – none of whom had known cardiac disease and all of whom were on antiretroviral therapy (ART) – was greater than that in HIV-negative individuals having matching Framingham Risk Scores (2.23 vs. 1.89, P = .0003). Moreover, it was about equal to that in HIV-negative individuals who had known atherosclerosis (2.13).

The findings were the same when only HIV-positive patients having an undetectable viral load – the large majority of those studied – were included in analyses, reported coinvestigator Dr. Steven Grinspoon, director of the Program in Nutritional Metabolism at Massachusetts General Hospital, Boston.

"The HIV-infected patients, essentially with total virological suppression and very low Framingham Risk Scores – a group that you would ordinarily not be particularly concerned about – had very significant arterial inflammation compared to the Framingham Risk Score–matched controls," he commented. "Moreover, this group of HIV-infected patients basically had the same degree of arterial inflammation as the group of non-HIV patients with known cardiovascular disease [CVD], except that the HIV patients didn’t have known CVD."

Previous research has suggested that arterial FDG uptake like that observed is due to macrophage accumulation at the interface between the lipid core and the fibrous cap in atherosclerotic plaques (Circulation 2002;105:2708-11). And results of the new study indeed showed that arterial inflammation in the HIV-positive group was correlated with levels of soluble CD163, a marker of monocyte activation. Dr. Grinspoon speculated that the heightened arterial inflammation may thus reflect chronic immune activation.

"Increased arterial inflammation in well-controlled subjects on ART is likely to contribute to increased CVD rates in this population," he maintained. "Strategies to target this inflammation, in addition to targeting traditional risk factors, including potential strategies to reduce monocyte activation, may be useful and should be investigated."

Session attendees questioned whether there was a confounding effect of statins, which are known to be anti-inflammatory and were used by none of the HIV-positive group, a quarter of the risk-matched HIV-negative group, and two-thirds of the HIV-negative group with known atherosclerosis. But Dr. Grinspoon noted that several analyses taking statin use into account yielded the same results.

When asked if he had any hypotheses as to what is activating the monocytes and whether microbes may have a role, he replied, "We are just beginning to look at some of the other markers. The whole entire cascade of macrophage activation and [microbial translocation] needs to be looked at more carefully."

Another attendee wondered if the duration of HIV infection influenced inflammation, given that most patients studied had been infected for at least a decade. "It would be absolutely fascinating ... to look at ART-naïve patients at the height of their [viral levels]," Dr. Grinspoon replied. "I would predict that the elevation will be even higher in those and that going on to ART will slam it down, and then it festers along at a certain kind of low-grade level. Our point in this study is that festering along is a problem because there seems to be at least arterial inflammation, even when you think, ‘Oh, the patient is fine, their viral load is suppressed.’ "

The investigators enrolled in the study 27 HIV-positive patients free of known cardiac disease who were on stable ART and did not have any opportunistic infections; 27 HIV-negative individuals matched for age, sex, and Framingham Risk Score who had no known atherosclerosis; and 27 HIV-negative patients matched for sex who had known atherosclerosis.

On average, the members of the HIV-positive group were 52 years old, had been infected for 16 years, and had been on ART for 12 years, according to Dr. Grinspoon, who disclosed no relevant conflicts of interest related to the research. Their mean CD4 count was 592 cells/mm³, and three-fourths had undetectable HIV RNA. Their average Framingham Risk Score was 6.4.

The significantly greater inflammation in the HIV-positive group than in the risk-matched HIV-negative group was evident across a variety of subgroups, such as individuals not having any coronary calcium, nonsmokers, those not taking statins, and those having an undetectable viral load.

And in a multivariate regression analysis, HIV positivity remained significantly associated with greater arterial inflammation after potential confounders, such as coronary calcium score and statin use, were controlled for. "So [HIV positivity] seemed to be adding independently to these things," Dr. Grinspoon noted.

In the HIV-positive group, arterial inflammation did not differ with use of various classes of ART drugs patients were taking, for example, between users vs. nonusers of protease inhibitors.

In an analysis of immune and inflammatory factors in the HIV-positive group, monocyte activation, as indicated by higher soluble CD163 levels, was significantly correlated with inflammation (P = .03). In contrast, C-reactive protein, d-dimer, and measures of HIV severity were not.

Dr. Grinspoon reported having no relevant conflicts of interest.

SEATTLE – HIV-infected individuals have increased arterial inflammation compared with their uninfected counterparts with the same levels of traditional cardiovascular risk factors, even when the infection is so well controlled that the virus is undetectable.

This was among the key findings of an observational study of 81 individuals who underwent fluorodeoxyglucose positron emission tomography (FDG-PET). Inflammation in the thoracic aorta was assessed from the target-to-background ratio of tracer uptake.

Courtesy Dr. Tom Folks, NIAID/National Institutes of Health

Study results, reported at the Conference on Retroviruses and Opportunistic Infections, showed that inflammation in the HIV-positive individuals – none of whom had known cardiac disease and all of whom were on antiretroviral therapy (ART) – was greater than that in HIV-negative individuals having matching Framingham Risk Scores (2.23 vs. 1.89, P = .0003). Moreover, it was about equal to that in HIV-negative individuals who had known atherosclerosis (2.13).

The findings were the same when only HIV-positive patients having an undetectable viral load – the large majority of those studied – were included in analyses, reported coinvestigator Dr. Steven Grinspoon, director of the Program in Nutritional Metabolism at Massachusetts General Hospital, Boston.

"The HIV-infected patients, essentially with total virological suppression and very low Framingham Risk Scores – a group that you would ordinarily not be particularly concerned about – had very significant arterial inflammation compared to the Framingham Risk Score–matched controls," he commented. "Moreover, this group of HIV-infected patients basically had the same degree of arterial inflammation as the group of non-HIV patients with known cardiovascular disease [CVD], except that the HIV patients didn’t have known CVD."

Previous research has suggested that arterial FDG uptake like that observed is due to macrophage accumulation at the interface between the lipid core and the fibrous cap in atherosclerotic plaques (Circulation 2002;105:2708-11). And results of the new study indeed showed that arterial inflammation in the HIV-positive group was correlated with levels of soluble CD163, a marker of monocyte activation. Dr. Grinspoon speculated that the heightened arterial inflammation may thus reflect chronic immune activation.

"Increased arterial inflammation in well-controlled subjects on ART is likely to contribute to increased CVD rates in this population," he maintained. "Strategies to target this inflammation, in addition to targeting traditional risk factors, including potential strategies to reduce monocyte activation, may be useful and should be investigated."

Session attendees questioned whether there was a confounding effect of statins, which are known to be anti-inflammatory and were used by none of the HIV-positive group, a quarter of the risk-matched HIV-negative group, and two-thirds of the HIV-negative group with known atherosclerosis. But Dr. Grinspoon noted that several analyses taking statin use into account yielded the same results.

When asked if he had any hypotheses as to what is activating the monocytes and whether microbes may have a role, he replied, "We are just beginning to look at some of the other markers. The whole entire cascade of macrophage activation and [microbial translocation] needs to be looked at more carefully."

Another attendee wondered if the duration of HIV infection influenced inflammation, given that most patients studied had been infected for at least a decade. "It would be absolutely fascinating ... to look at ART-naïve patients at the height of their [viral levels]," Dr. Grinspoon replied. "I would predict that the elevation will be even higher in those and that going on to ART will slam it down, and then it festers along at a certain kind of low-grade level. Our point in this study is that festering along is a problem because there seems to be at least arterial inflammation, even when you think, ‘Oh, the patient is fine, their viral load is suppressed.’ "

The investigators enrolled in the study 27 HIV-positive patients free of known cardiac disease who were on stable ART and did not have any opportunistic infections; 27 HIV-negative individuals matched for age, sex, and Framingham Risk Score who had no known atherosclerosis; and 27 HIV-negative patients matched for sex who had known atherosclerosis.

On average, the members of the HIV-positive group were 52 years old, had been infected for 16 years, and had been on ART for 12 years, according to Dr. Grinspoon, who disclosed no relevant conflicts of interest related to the research. Their mean CD4 count was 592 cells/mm³, and three-fourths had undetectable HIV RNA. Their average Framingham Risk Score was 6.4.

The significantly greater inflammation in the HIV-positive group than in the risk-matched HIV-negative group was evident across a variety of subgroups, such as individuals not having any coronary calcium, nonsmokers, those not taking statins, and those having an undetectable viral load.

And in a multivariate regression analysis, HIV positivity remained significantly associated with greater arterial inflammation after potential confounders, such as coronary calcium score and statin use, were controlled for. "So [HIV positivity] seemed to be adding independently to these things," Dr. Grinspoon noted.

In the HIV-positive group, arterial inflammation did not differ with use of various classes of ART drugs patients were taking, for example, between users vs. nonusers of protease inhibitors.

In an analysis of immune and inflammatory factors in the HIV-positive group, monocyte activation, as indicated by higher soluble CD163 levels, was significantly correlated with inflammation (P = .03). In contrast, C-reactive protein, d-dimer, and measures of HIV severity were not.

Dr. Grinspoon reported having no relevant conflicts of interest.

SEATTLE – HIV-infected individuals have increased arterial inflammation compared with their uninfected counterparts with the same levels of traditional cardiovascular risk factors, even when the infection is so well controlled that the virus is undetectable.

This was among the key findings of an observational study of 81 individuals who underwent fluorodeoxyglucose positron emission tomography (FDG-PET). Inflammation in the thoracic aorta was assessed from the target-to-background ratio of tracer uptake.

Courtesy Dr. Tom Folks, NIAID/National Institutes of Health

Study results, reported at the Conference on Retroviruses and Opportunistic Infections, showed that inflammation in the HIV-positive individuals – none of whom had known cardiac disease and all of whom were on antiretroviral therapy (ART) – was greater than that in HIV-negative individuals having matching Framingham Risk Scores (2.23 vs. 1.89, P = .0003). Moreover, it was about equal to that in HIV-negative individuals who had known atherosclerosis (2.13).

The findings were the same when only HIV-positive patients having an undetectable viral load – the large majority of those studied – were included in analyses, reported coinvestigator Dr. Steven Grinspoon, director of the Program in Nutritional Metabolism at Massachusetts General Hospital, Boston.

"The HIV-infected patients, essentially with total virological suppression and very low Framingham Risk Scores – a group that you would ordinarily not be particularly concerned about – had very significant arterial inflammation compared to the Framingham Risk Score–matched controls," he commented. "Moreover, this group of HIV-infected patients basically had the same degree of arterial inflammation as the group of non-HIV patients with known cardiovascular disease [CVD], except that the HIV patients didn’t have known CVD."

Previous research has suggested that arterial FDG uptake like that observed is due to macrophage accumulation at the interface between the lipid core and the fibrous cap in atherosclerotic plaques (Circulation 2002;105:2708-11). And results of the new study indeed showed that arterial inflammation in the HIV-positive group was correlated with levels of soluble CD163, a marker of monocyte activation. Dr. Grinspoon speculated that the heightened arterial inflammation may thus reflect chronic immune activation.

"Increased arterial inflammation in well-controlled subjects on ART is likely to contribute to increased CVD rates in this population," he maintained. "Strategies to target this inflammation, in addition to targeting traditional risk factors, including potential strategies to reduce monocyte activation, may be useful and should be investigated."

Session attendees questioned whether there was a confounding effect of statins, which are known to be anti-inflammatory and were used by none of the HIV-positive group, a quarter of the risk-matched HIV-negative group, and two-thirds of the HIV-negative group with known atherosclerosis. But Dr. Grinspoon noted that several analyses taking statin use into account yielded the same results.

When asked if he had any hypotheses as to what is activating the monocytes and whether microbes may have a role, he replied, "We are just beginning to look at some of the other markers. The whole entire cascade of macrophage activation and [microbial translocation] needs to be looked at more carefully."

Another attendee wondered if the duration of HIV infection influenced inflammation, given that most patients studied had been infected for at least a decade. "It would be absolutely fascinating ... to look at ART-naïve patients at the height of their [viral levels]," Dr. Grinspoon replied. "I would predict that the elevation will be even higher in those and that going on to ART will slam it down, and then it festers along at a certain kind of low-grade level. Our point in this study is that festering along is a problem because there seems to be at least arterial inflammation, even when you think, ‘Oh, the patient is fine, their viral load is suppressed.’ "

The investigators enrolled in the study 27 HIV-positive patients free of known cardiac disease who were on stable ART and did not have any opportunistic infections; 27 HIV-negative individuals matched for age, sex, and Framingham Risk Score who had no known atherosclerosis; and 27 HIV-negative patients matched for sex who had known atherosclerosis.

On average, the members of the HIV-positive group were 52 years old, had been infected for 16 years, and had been on ART for 12 years, according to Dr. Grinspoon, who disclosed no relevant conflicts of interest related to the research. Their mean CD4 count was 592 cells/mm³, and three-fourths had undetectable HIV RNA. Their average Framingham Risk Score was 6.4.

The significantly greater inflammation in the HIV-positive group than in the risk-matched HIV-negative group was evident across a variety of subgroups, such as individuals not having any coronary calcium, nonsmokers, those not taking statins, and those having an undetectable viral load.

And in a multivariate regression analysis, HIV positivity remained significantly associated with greater arterial inflammation after potential confounders, such as coronary calcium score and statin use, were controlled for. "So [HIV positivity] seemed to be adding independently to these things," Dr. Grinspoon noted.

In the HIV-positive group, arterial inflammation did not differ with use of various classes of ART drugs patients were taking, for example, between users vs. nonusers of protease inhibitors.

In an analysis of immune and inflammatory factors in the HIV-positive group, monocyte activation, as indicated by higher soluble CD163 levels, was significantly correlated with inflammation (P = .03). In contrast, C-reactive protein, d-dimer, and measures of HIV severity were not.

Dr. Grinspoon reported having no relevant conflicts of interest.

SEATTLE – HIV-positive patients who have asymptomatic neurocognitive impairment may require especially close follow-up because of a sharply elevated risk of progression to symptomatic disease, according to an analysis from the CHARTER longitudinal cohort study.

At baseline, 35% of the 347 patients studied had neurocognitive impairments on testing but did not have any self-reported or observed declines in everyday functioning, and were thus classified as having asymptomatic neurocognitive impairment (ANI).

After a median follow-up of nearly 4 years, these patients had a 2.2- to 5.3-fold higher risk of developing symptomatic HIV-associated neurocognitive disorder relative to their counterparts who were neurocognitively normal, Dr. Igor Grant reported at the Conference on Retroviruses and Opportunistic Infections.

"The CHARTER study suggests that people with ANI do tend to progress to symptomatic status more frequently than people who don’t have any cognitive impairment," he commented. "ANI could be a harbinger for some underlying process that is worthy of monitoring."

In additional findings, certain other groups of patients defined by sociodemographic and HIV-related factors – women, substance abusers, and those with lower nadir CD4 counts, for example – also had an elevated risk of progression to the point of having symptoms.

Session attendee Dr. Lewis Haddow from the University College London wondered about the blinding of patients to their impairment on testing. "Could those with a label of ANI perhaps have overreported things on the self-report scale and subsequent follow-up?" he asked.

"They were not told their results, so those with ANI would not know it," replied Dr. Grant, who is professor and executive vice chair of the department of psychiatry at the University of California, San Diego.

Giving some study background, he noted that frank dementia in HIV-positive patients is uncommon today with effective antiretroviral therapy, but milder forms of impairment are still observed. "There has been concern among investigators as to whether particularly this entity of asymptomatic neurocognitive impairment, A, is real; and B, has clinical significance or any kind of predictive validity," he commented.

The CHARTER study was a multicenter study among HIV-positive patients receiving care in the era of highly active antiretroviral therapy. Every 6 months, a patient subset was assessed with a comprehensive battery of neurocognitive and other tests.

Symptomatic neurocognitive disorder was ascertained from self-report (requiring impairments on both the Patient Assessment of Own Functioning Inventory and Activities of Daily Living) and performance (requiring impairment on the Medication Management Test–Revised or on the Valpar System 3000 Work Samples and Computerized Assessment).

On average, the patients were about 43 years old and had been HIV positive for roughly a decade. Approximately 70% were on antiretroviral therapy; 82% were male, and 46% were white. With a median follow-up of 45 months, 32% developed symptomatic neurocognitive disorder.

After adjustment for education, estimated verbal IQ, and comorbidity classification, patients with ANI had an increased risk of symptomatic neurocognitive disorder based on self-report only (relative risk, 2.2; P = .005) and performance only (RR, 5.3, P less than .0001).

Certain baseline sociodemographic factors including age, female gender, low levels of education, and the presence of comorbidity as well as certain HIV-related factors including low nadir CD4 count and presence of AIDS also predicted decline to symptomatic status.

The investigators have not yet looked at the predictive performance of individual measures of neurocognitive function, according to Dr. Grant, who disclosed no relevant conflicts of interest. Also, they have not assessed virologic suppression as a predictor, but being on antiretroviral therapy did not predict decline to symptomatic neurocognitive disorder.

SEATTLE – HIV-positive patients who have asymptomatic neurocognitive impairment may require especially close follow-up because of a sharply elevated risk of progression to symptomatic disease, according to an analysis from the CHARTER longitudinal cohort study.

At baseline, 35% of the 347 patients studied had neurocognitive impairments on testing but did not have any self-reported or observed declines in everyday functioning, and were thus classified as having asymptomatic neurocognitive impairment (ANI).

After a median follow-up of nearly 4 years, these patients had a 2.2- to 5.3-fold higher risk of developing symptomatic HIV-associated neurocognitive disorder relative to their counterparts who were neurocognitively normal, Dr. Igor Grant reported at the Conference on Retroviruses and Opportunistic Infections.

"The CHARTER study suggests that people with ANI do tend to progress to symptomatic status more frequently than people who don’t have any cognitive impairment," he commented. "ANI could be a harbinger for some underlying process that is worthy of monitoring."

In additional findings, certain other groups of patients defined by sociodemographic and HIV-related factors – women, substance abusers, and those with lower nadir CD4 counts, for example – also had an elevated risk of progression to the point of having symptoms.

Session attendee Dr. Lewis Haddow from the University College London wondered about the blinding of patients to their impairment on testing. "Could those with a label of ANI perhaps have overreported things on the self-report scale and subsequent follow-up?" he asked.

"They were not told their results, so those with ANI would not know it," replied Dr. Grant, who is professor and executive vice chair of the department of psychiatry at the University of California, San Diego.

Giving some study background, he noted that frank dementia in HIV-positive patients is uncommon today with effective antiretroviral therapy, but milder forms of impairment are still observed. "There has been concern among investigators as to whether particularly this entity of asymptomatic neurocognitive impairment, A, is real; and B, has clinical significance or any kind of predictive validity," he commented.

The CHARTER study was a multicenter study among HIV-positive patients receiving care in the era of highly active antiretroviral therapy. Every 6 months, a patient subset was assessed with a comprehensive battery of neurocognitive and other tests.

Symptomatic neurocognitive disorder was ascertained from self-report (requiring impairments on both the Patient Assessment of Own Functioning Inventory and Activities of Daily Living) and performance (requiring impairment on the Medication Management Test–Revised or on the Valpar System 3000 Work Samples and Computerized Assessment).

On average, the patients were about 43 years old and had been HIV positive for roughly a decade. Approximately 70% were on antiretroviral therapy; 82% were male, and 46% were white. With a median follow-up of 45 months, 32% developed symptomatic neurocognitive disorder.

After adjustment for education, estimated verbal IQ, and comorbidity classification, patients with ANI had an increased risk of symptomatic neurocognitive disorder based on self-report only (relative risk, 2.2; P = .005) and performance only (RR, 5.3, P less than .0001).

Certain baseline sociodemographic factors including age, female gender, low levels of education, and the presence of comorbidity as well as certain HIV-related factors including low nadir CD4 count and presence of AIDS also predicted decline to symptomatic status.

The investigators have not yet looked at the predictive performance of individual measures of neurocognitive function, according to Dr. Grant, who disclosed no relevant conflicts of interest. Also, they have not assessed virologic suppression as a predictor, but being on antiretroviral therapy did not predict decline to symptomatic neurocognitive disorder.

SEATTLE – HIV-positive patients who have asymptomatic neurocognitive impairment may require especially close follow-up because of a sharply elevated risk of progression to symptomatic disease, according to an analysis from the CHARTER longitudinal cohort study.

At baseline, 35% of the 347 patients studied had neurocognitive impairments on testing but did not have any self-reported or observed declines in everyday functioning, and were thus classified as having asymptomatic neurocognitive impairment (ANI).

After a median follow-up of nearly 4 years, these patients had a 2.2- to 5.3-fold higher risk of developing symptomatic HIV-associated neurocognitive disorder relative to their counterparts who were neurocognitively normal, Dr. Igor Grant reported at the Conference on Retroviruses and Opportunistic Infections.

"The CHARTER study suggests that people with ANI do tend to progress to symptomatic status more frequently than people who don’t have any cognitive impairment," he commented. "ANI could be a harbinger for some underlying process that is worthy of monitoring."

In additional findings, certain other groups of patients defined by sociodemographic and HIV-related factors – women, substance abusers, and those with lower nadir CD4 counts, for example – also had an elevated risk of progression to the point of having symptoms.

Session attendee Dr. Lewis Haddow from the University College London wondered about the blinding of patients to their impairment on testing. "Could those with a label of ANI perhaps have overreported things on the self-report scale and subsequent follow-up?" he asked.

"They were not told their results, so those with ANI would not know it," replied Dr. Grant, who is professor and executive vice chair of the department of psychiatry at the University of California, San Diego.

Giving some study background, he noted that frank dementia in HIV-positive patients is uncommon today with effective antiretroviral therapy, but milder forms of impairment are still observed. "There has been concern among investigators as to whether particularly this entity of asymptomatic neurocognitive impairment, A, is real; and B, has clinical significance or any kind of predictive validity," he commented.

The CHARTER study was a multicenter study among HIV-positive patients receiving care in the era of highly active antiretroviral therapy. Every 6 months, a patient subset was assessed with a comprehensive battery of neurocognitive and other tests.

Symptomatic neurocognitive disorder was ascertained from self-report (requiring impairments on both the Patient Assessment of Own Functioning Inventory and Activities of Daily Living) and performance (requiring impairment on the Medication Management Test–Revised or on the Valpar System 3000 Work Samples and Computerized Assessment).

On average, the patients were about 43 years old and had been HIV positive for roughly a decade. Approximately 70% were on antiretroviral therapy; 82% were male, and 46% were white. With a median follow-up of 45 months, 32% developed symptomatic neurocognitive disorder.

After adjustment for education, estimated verbal IQ, and comorbidity classification, patients with ANI had an increased risk of symptomatic neurocognitive disorder based on self-report only (relative risk, 2.2; P = .005) and performance only (RR, 5.3, P less than .0001).

Certain baseline sociodemographic factors including age, female gender, low levels of education, and the presence of comorbidity as well as certain HIV-related factors including low nadir CD4 count and presence of AIDS also predicted decline to symptomatic status.

The investigators have not yet looked at the predictive performance of individual measures of neurocognitive function, according to Dr. Grant, who disclosed no relevant conflicts of interest. Also, they have not assessed virologic suppression as a predictor, but being on antiretroviral therapy did not predict decline to symptomatic neurocognitive disorder.

A new, rapid, point-of-care genetic test may help tailor antiplatelet therapy after percutaneous coronary intervention, so that patients receive an agent providing the best balance of benefits and risks for them, suggests the randomized, proof-of-concept RAPID-GENE trial.

The 200 trial patients who underwent PCI for acute coronary syndromes or stable angina were assigned evenly to a standard treatment arm or a tailored-treatment arm.

The former all received clopidogrel. The latter first had rapid genotyping for the CYP2C19*2 loss-of-function allele, which confers inadequate inhibition of the platelet P2Y12 receptor and increased rates of major adverse events among patients taking clopidogrel after PCI. Carriers of the allele were given prasugrel – a novel P2Y12 inhibitor that provides more potent platelet inhibition but with the trade-off of increased bleeding – whereas noncarriers were given clopidogrel. All trial patients received aspirin as well.

Trial results, reported online first in the Lancet, showed that after a week of dual antiplatelet therapy, nearly a third of CYP2C19*2 carriers who were given standard treatment had high on-treatment platelet reactivity, a marker of increased adverse cardiovascular events. This compared with none of their counterparts who received tailored treatment, reported Dr. Jason D. Roberts and his colleagues at the University of Ottawa Heart Institute (Lancet 2012 March 29 [doi:10.1016/S0140-6736(12)60161-5]).

"As far as we are aware, our study is the first to validate and to show clinical use of point-of-care genetic testing. It is the first randomised investigation of selective use of prasugrel in CYP2C19*2 carriers after PCI," wrote the investigators.

"Our findings suggest that personalisation of antiplatelet therapy might reduce adverse ischaemic outcomes; use of prasugrel only in high-risk individuals might also minimise adverse bleeding events. The development of practical point-of-care genetic testing in our study will help to integrate genetics into the clinical setting and will allow large-scale investigations to definitively assess the value of pharmacogenetic strategies," they wrote.

In an accompanying comment, Amber L. Beitelshees, Pharm.D., of the University of Maryland, Baltimore, noted that "widespread clinical implementation of clopidogrel pharmacogenetics has not progressed at the expected pace, and the RAPID GENE study provides much-needed impetus by showing that genotyping can be done in a timely manner and incorporated into the clinical workflow as we wait for the results of large outcome-driven randomised trials."

However, she also pointed out that the study "had a surrogate end point of ex-vivo platelet aggregation, so whether genotype-guided treatment will indeed improve major adverse cardiovascular outcomes is yet to be established."

In the trial, CYP2C19*2 allele status was assessed with Spartan Biosciences’ RX CYP2C19, a bedside test that uses a buccal swab, can be performed by clinicians having no previous training in genetic laboratory techniques, and yields results in about 1 hour.

All patients in the standard treatment group and noncarriers in the tailored-treatment group received 75 mg clopidogrel (Plavix) daily. Carriers in the tailored-treatment group received 10 mg prasugrel (Effient) daily.

Trial results showed that 25% of patients in the standard treatment group and 24% of patients in the tailored-treatment group carried at least one CYP2C19*2 allele.

The proportion of carriers who had high on-treatment platelet reactivity (defined as a P2Y12 reactivity unit [PRU] value greater than 234) after a week of dual antiplatelet therapy – the trial’s primary end point – was significantly lower for those in the tailored-treatment group (0% vs. 30%).

The findings were similar when a PRU value of 208 was used to define high on-treatment platelet reactivity (4% vs. 48%).

Additionally, compared with the reference standard of direct DNA sequencing, the point-of-care genetic test had excellent sensitivity (100%) and specificity (99%).

"For the first time in clinical medicine, we have proven that a simple bedside test can enable rapid genetic testing and subsequent personalised therapy. This is an important step towards integrating pharmacogenomic strategies into clinical care," senior author Dr. Derek Y. F. So commented in a prepared statement.

Dr. So disclosed receiving unrestricted research grants for physician-initiated studies from Sanofi-Aventis Canada, Abbott Vascular Canada, and Spartan Biosciences, and honoraria from Eli Lilly Canada. The trial was funded by Spartan Biosciences. Dr. Beitelshees disclosed having no relevant conflicts of interest.

A new, rapid, point-of-care genetic test may help tailor antiplatelet therapy after percutaneous coronary intervention, so that patients receive an agent providing the best balance of benefits and risks for them, suggests the randomized, proof-of-concept RAPID-GENE trial.

The 200 trial patients who underwent PCI for acute coronary syndromes or stable angina were assigned evenly to a standard treatment arm or a tailored-treatment arm.

The former all received clopidogrel. The latter first had rapid genotyping for the CYP2C19*2 loss-of-function allele, which confers inadequate inhibition of the platelet P2Y12 receptor and increased rates of major adverse events among patients taking clopidogrel after PCI. Carriers of the allele were given prasugrel – a novel P2Y12 inhibitor that provides more potent platelet inhibition but with the trade-off of increased bleeding – whereas noncarriers were given clopidogrel. All trial patients received aspirin as well.

Trial results, reported online first in the Lancet, showed that after a week of dual antiplatelet therapy, nearly a third of CYP2C19*2 carriers who were given standard treatment had high on-treatment platelet reactivity, a marker of increased adverse cardiovascular events. This compared with none of their counterparts who received tailored treatment, reported Dr. Jason D. Roberts and his colleagues at the University of Ottawa Heart Institute (Lancet 2012 March 29 [doi:10.1016/S0140-6736(12)60161-5]).

"As far as we are aware, our study is the first to validate and to show clinical use of point-of-care genetic testing. It is the first randomised investigation of selective use of prasugrel in CYP2C19*2 carriers after PCI," wrote the investigators.

"Our findings suggest that personalisation of antiplatelet therapy might reduce adverse ischaemic outcomes; use of prasugrel only in high-risk individuals might also minimise adverse bleeding events. The development of practical point-of-care genetic testing in our study will help to integrate genetics into the clinical setting and will allow large-scale investigations to definitively assess the value of pharmacogenetic strategies," they wrote.

In an accompanying comment, Amber L. Beitelshees, Pharm.D., of the University of Maryland, Baltimore, noted that "widespread clinical implementation of clopidogrel pharmacogenetics has not progressed at the expected pace, and the RAPID GENE study provides much-needed impetus by showing that genotyping can be done in a timely manner and incorporated into the clinical workflow as we wait for the results of large outcome-driven randomised trials."

However, she also pointed out that the study "had a surrogate end point of ex-vivo platelet aggregation, so whether genotype-guided treatment will indeed improve major adverse cardiovascular outcomes is yet to be established."

In the trial, CYP2C19*2 allele status was assessed with Spartan Biosciences’ RX CYP2C19, a bedside test that uses a buccal swab, can be performed by clinicians having no previous training in genetic laboratory techniques, and yields results in about 1 hour.

All patients in the standard treatment group and noncarriers in the tailored-treatment group received 75 mg clopidogrel (Plavix) daily. Carriers in the tailored-treatment group received 10 mg prasugrel (Effient) daily.

Trial results showed that 25% of patients in the standard treatment group and 24% of patients in the tailored-treatment group carried at least one CYP2C19*2 allele.

The proportion of carriers who had high on-treatment platelet reactivity (defined as a P2Y12 reactivity unit [PRU] value greater than 234) after a week of dual antiplatelet therapy – the trial’s primary end point – was significantly lower for those in the tailored-treatment group (0% vs. 30%).

The findings were similar when a PRU value of 208 was used to define high on-treatment platelet reactivity (4% vs. 48%).

Additionally, compared with the reference standard of direct DNA sequencing, the point-of-care genetic test had excellent sensitivity (100%) and specificity (99%).

"For the first time in clinical medicine, we have proven that a simple bedside test can enable rapid genetic testing and subsequent personalised therapy. This is an important step towards integrating pharmacogenomic strategies into clinical care," senior author Dr. Derek Y. F. So commented in a prepared statement.

Dr. So disclosed receiving unrestricted research grants for physician-initiated studies from Sanofi-Aventis Canada, Abbott Vascular Canada, and Spartan Biosciences, and honoraria from Eli Lilly Canada. The trial was funded by Spartan Biosciences. Dr. Beitelshees disclosed having no relevant conflicts of interest.

A new, rapid, point-of-care genetic test may help tailor antiplatelet therapy after percutaneous coronary intervention, so that patients receive an agent providing the best balance of benefits and risks for them, suggests the randomized, proof-of-concept RAPID-GENE trial.

The 200 trial patients who underwent PCI for acute coronary syndromes or stable angina were assigned evenly to a standard treatment arm or a tailored-treatment arm.

The former all received clopidogrel. The latter first had rapid genotyping for the CYP2C19*2 loss-of-function allele, which confers inadequate inhibition of the platelet P2Y12 receptor and increased rates of major adverse events among patients taking clopidogrel after PCI. Carriers of the allele were given prasugrel – a novel P2Y12 inhibitor that provides more potent platelet inhibition but with the trade-off of increased bleeding – whereas noncarriers were given clopidogrel. All trial patients received aspirin as well.

Trial results, reported online first in the Lancet, showed that after a week of dual antiplatelet therapy, nearly a third of CYP2C19*2 carriers who were given standard treatment had high on-treatment platelet reactivity, a marker of increased adverse cardiovascular events. This compared with none of their counterparts who received tailored treatment, reported Dr. Jason D. Roberts and his colleagues at the University of Ottawa Heart Institute (Lancet 2012 March 29 [doi:10.1016/S0140-6736(12)60161-5]).

"As far as we are aware, our study is the first to validate and to show clinical use of point-of-care genetic testing. It is the first randomised investigation of selective use of prasugrel in CYP2C19*2 carriers after PCI," wrote the investigators.

"Our findings suggest that personalisation of antiplatelet therapy might reduce adverse ischaemic outcomes; use of prasugrel only in high-risk individuals might also minimise adverse bleeding events. The development of practical point-of-care genetic testing in our study will help to integrate genetics into the clinical setting and will allow large-scale investigations to definitively assess the value of pharmacogenetic strategies," they wrote.

In an accompanying comment, Amber L. Beitelshees, Pharm.D., of the University of Maryland, Baltimore, noted that "widespread clinical implementation of clopidogrel pharmacogenetics has not progressed at the expected pace, and the RAPID GENE study provides much-needed impetus by showing that genotyping can be done in a timely manner and incorporated into the clinical workflow as we wait for the results of large outcome-driven randomised trials."

However, she also pointed out that the study "had a surrogate end point of ex-vivo platelet aggregation, so whether genotype-guided treatment will indeed improve major adverse cardiovascular outcomes is yet to be established."

In the trial, CYP2C19*2 allele status was assessed with Spartan Biosciences’ RX CYP2C19, a bedside test that uses a buccal swab, can be performed by clinicians having no previous training in genetic laboratory techniques, and yields results in about 1 hour.

All patients in the standard treatment group and noncarriers in the tailored-treatment group received 75 mg clopidogrel (Plavix) daily. Carriers in the tailored-treatment group received 10 mg prasugrel (Effient) daily.

Trial results showed that 25% of patients in the standard treatment group and 24% of patients in the tailored-treatment group carried at least one CYP2C19*2 allele.

The proportion of carriers who had high on-treatment platelet reactivity (defined as a P2Y12 reactivity unit [PRU] value greater than 234) after a week of dual antiplatelet therapy – the trial’s primary end point – was significantly lower for those in the tailored-treatment group (0% vs. 30%).

The findings were similar when a PRU value of 208 was used to define high on-treatment platelet reactivity (4% vs. 48%).

Additionally, compared with the reference standard of direct DNA sequencing, the point-of-care genetic test had excellent sensitivity (100%) and specificity (99%).

"For the first time in clinical medicine, we have proven that a simple bedside test can enable rapid genetic testing and subsequent personalised therapy. This is an important step towards integrating pharmacogenomic strategies into clinical care," senior author Dr. Derek Y. F. So commented in a prepared statement.

Dr. So disclosed receiving unrestricted research grants for physician-initiated studies from Sanofi-Aventis Canada, Abbott Vascular Canada, and Spartan Biosciences, and honoraria from Eli Lilly Canada. The trial was funded by Spartan Biosciences. Dr. Beitelshees disclosed having no relevant conflicts of interest.

SEATTLE – Switching to an antiretroviral regimen that contains tenofovir may adversely affect the skeletal health of HIV-positive patients, according to a new analysis reported at the Conference on Retroviruses and Opportunistic Infections.

The analysis came from the Bone Biomarker Substudy of the multicenter PREPARE trial, in which HIV-positive patients taking first-line zidovudine-lamivudine (AZT-3TC) who had virologic suppression were randomized to either continue on that therapy or switch to tenofovir-emtricitabine (TDF-FTC).

The 54 patients in the substudy underwent serial measurements of bone biomarkers and had dual-energy x-ray absorptiometry (DXA) scanning at baseline and 48 weeks.

Main results showed that the group that switched therapy had increases in markers of bone turnover and lost 2% of the bone mineral density (BMD) in their lumbar spine, reported lead investigator Dr. Aoife G. Cotter of University College Dublin. In contrast, those who continued on the same therapy did not have significant changes in these measures.

"The impact of these changes on future and overall risk of fracture is unknown, and prospective longitudinal studies are required to answer this question," she commented. Also, "while we show that tenofovir affects bone metabolism in vivo, whether this is a direct effect of tenofovir on bone cells versus an indirect effect of tenofovir on bone via the renal tubules remains to be answered."

Session attendee Dr. Todd Brown of Johns Hopkins University, Baltimore, noted that tenofovir has heterogeneous effects on bone across patients, and it would be nice to have a marker for early identification of patients who will lose BMD. "One way to do that potentially is with bone markers, so I was wondering if early absolute levels or early changes in bone markers predicted bone loss with tenofovir," he said.

The investigators did not assess that association, but a similar study looking at regimen simplification, called the STEAL study, did and found no correlation, according to Dr. Cotter. "However, when you look at our medians [for biomarker levels] plotted over time, the changes really weren’t maximal until at least 24 weeks, so we would need to have looked at changes up until at least 24 weeks to see if they correlated," she added.

Another attendee, Dr. Michael Yin of Columbia University Medical Center in New York, asked, "Are there plans to follow up with another DXA at a later date, because this is quite similar to the loss that you experience with initiation of ART, although in a different setting. It would be interesting to see whether or not the bone loss continues." Additionally, he wondered if the investigators were looking at other biomarkers.

"There are no plans that I know of to repeat DXA scans on these subjects or to increase the duration of follow-up," Dr. Cotter replied. "We do, however, have samples left and are currently performing vitamin D and parathyroid hormone analysis."

Adult HIV-positive patients were eligible for the PREPARE trial if they had been on a zidovudine-lamivudine–containing regimen as their first treatment for more than 2 years and had had a viral load of fewer than 50 copies of HIV RNA/mL for more than 6 months.

They had a median age of about 46 years, and the majority were male and white. They had been on zidovudine and lamivudine (brand names Retrovir and Epivir) for a median of roughly 5.5 years.

Results showed that compared with the group that continued on zidovudine-lamivudine, the group that switched to tenofovir plus emtricitabine (brand names Viread and Emtriva) had greater changes between baseline and week 48 in three biomarkers of bone turnover: type 1 collagen cross-linked C-telopeptide (P = .0005), osteocalcin (P less than .0001), and procollagen type 1 N-terminal propeptide (P less than .0001).

BMD of the lumbar spine fell by 2.04% from baseline in the group that switched (P = .01) but changed little in the group that continued on the original regimen, resulting in a significant difference between them (P = .03). Neither group had a significant change from baseline in BMD of the femoral neck.

The changes in levels of osteocalcin and procollagen type 1 N-terminal propeptide over the 48-week period were significantly inversely correlated with loss of BMD in the lumbar spine.

In a multivariate analysis adjusted for baseline biomarker level, sex, and ethnicity, the switch from zidovudine-lamivudine to tenofovir-emtricitabine was a significant independent predictor of changes in levels of all three biomarkers.

Among various study limitations, Dr. Cotter acknowledged, was "an absence of data on some classical risk factors, such as smoking and significant use of steroids." Also, "our follow-up was limited to 48 weeks; it would have been interesting to see what happened beyond that," she commented.

Dr. Cotter disclosed no relevant conflicts of interest. The PREPARE trial was supported by an unrestricted scientific grant from Gilead Sciences.

SEATTLE – Switching to an antiretroviral regimen that contains tenofovir may adversely affect the skeletal health of HIV-positive patients, according to a new analysis reported at the Conference on Retroviruses and Opportunistic Infections.

The analysis came from the Bone Biomarker Substudy of the multicenter PREPARE trial, in which HIV-positive patients taking first-line zidovudine-lamivudine (AZT-3TC) who had virologic suppression were randomized to either continue on that therapy or switch to tenofovir-emtricitabine (TDF-FTC).

The 54 patients in the substudy underwent serial measurements of bone biomarkers and had dual-energy x-ray absorptiometry (DXA) scanning at baseline and 48 weeks.

Main results showed that the group that switched therapy had increases in markers of bone turnover and lost 2% of the bone mineral density (BMD) in their lumbar spine, reported lead investigator Dr. Aoife G. Cotter of University College Dublin. In contrast, those who continued on the same therapy did not have significant changes in these measures.

"The impact of these changes on future and overall risk of fracture is unknown, and prospective longitudinal studies are required to answer this question," she commented. Also, "while we show that tenofovir affects bone metabolism in vivo, whether this is a direct effect of tenofovir on bone cells versus an indirect effect of tenofovir on bone via the renal tubules remains to be answered."

Session attendee Dr. Todd Brown of Johns Hopkins University, Baltimore, noted that tenofovir has heterogeneous effects on bone across patients, and it would be nice to have a marker for early identification of patients who will lose BMD. "One way to do that potentially is with bone markers, so I was wondering if early absolute levels or early changes in bone markers predicted bone loss with tenofovir," he said.

The investigators did not assess that association, but a similar study looking at regimen simplification, called the STEAL study, did and found no correlation, according to Dr. Cotter. "However, when you look at our medians [for biomarker levels] plotted over time, the changes really weren’t maximal until at least 24 weeks, so we would need to have looked at changes up until at least 24 weeks to see if they correlated," she added.

Another attendee, Dr. Michael Yin of Columbia University Medical Center in New York, asked, "Are there plans to follow up with another DXA at a later date, because this is quite similar to the loss that you experience with initiation of ART, although in a different setting. It would be interesting to see whether or not the bone loss continues." Additionally, he wondered if the investigators were looking at other biomarkers.

"There are no plans that I know of to repeat DXA scans on these subjects or to increase the duration of follow-up," Dr. Cotter replied. "We do, however, have samples left and are currently performing vitamin D and parathyroid hormone analysis."

Adult HIV-positive patients were eligible for the PREPARE trial if they had been on a zidovudine-lamivudine–containing regimen as their first treatment for more than 2 years and had had a viral load of fewer than 50 copies of HIV RNA/mL for more than 6 months.

They had a median age of about 46 years, and the majority were male and white. They had been on zidovudine and lamivudine (brand names Retrovir and Epivir) for a median of roughly 5.5 years.

Results showed that compared with the group that continued on zidovudine-lamivudine, the group that switched to tenofovir plus emtricitabine (brand names Viread and Emtriva) had greater changes between baseline and week 48 in three biomarkers of bone turnover: type 1 collagen cross-linked C-telopeptide (P = .0005), osteocalcin (P less than .0001), and procollagen type 1 N-terminal propeptide (P less than .0001).

BMD of the lumbar spine fell by 2.04% from baseline in the group that switched (P = .01) but changed little in the group that continued on the original regimen, resulting in a significant difference between them (P = .03). Neither group had a significant change from baseline in BMD of the femoral neck.

The changes in levels of osteocalcin and procollagen type 1 N-terminal propeptide over the 48-week period were significantly inversely correlated with loss of BMD in the lumbar spine.

In a multivariate analysis adjusted for baseline biomarker level, sex, and ethnicity, the switch from zidovudine-lamivudine to tenofovir-emtricitabine was a significant independent predictor of changes in levels of all three biomarkers.

Among various study limitations, Dr. Cotter acknowledged, was "an absence of data on some classical risk factors, such as smoking and significant use of steroids." Also, "our follow-up was limited to 48 weeks; it would have been interesting to see what happened beyond that," she commented.

Dr. Cotter disclosed no relevant conflicts of interest. The PREPARE trial was supported by an unrestricted scientific grant from Gilead Sciences.

SEATTLE – Switching to an antiretroviral regimen that contains tenofovir may adversely affect the skeletal health of HIV-positive patients, according to a new analysis reported at the Conference on Retroviruses and Opportunistic Infections.

The analysis came from the Bone Biomarker Substudy of the multicenter PREPARE trial, in which HIV-positive patients taking first-line zidovudine-lamivudine (AZT-3TC) who had virologic suppression were randomized to either continue on that therapy or switch to tenofovir-emtricitabine (TDF-FTC).

The 54 patients in the substudy underwent serial measurements of bone biomarkers and had dual-energy x-ray absorptiometry (DXA) scanning at baseline and 48 weeks.

Main results showed that the group that switched therapy had increases in markers of bone turnover and lost 2% of the bone mineral density (BMD) in their lumbar spine, reported lead investigator Dr. Aoife G. Cotter of University College Dublin. In contrast, those who continued on the same therapy did not have significant changes in these measures.

"The impact of these changes on future and overall risk of fracture is unknown, and prospective longitudinal studies are required to answer this question," she commented. Also, "while we show that tenofovir affects bone metabolism in vivo, whether this is a direct effect of tenofovir on bone cells versus an indirect effect of tenofovir on bone via the renal tubules remains to be answered."

Session attendee Dr. Todd Brown of Johns Hopkins University, Baltimore, noted that tenofovir has heterogeneous effects on bone across patients, and it would be nice to have a marker for early identification of patients who will lose BMD. "One way to do that potentially is with bone markers, so I was wondering if early absolute levels or early changes in bone markers predicted bone loss with tenofovir," he said.

The investigators did not assess that association, but a similar study looking at regimen simplification, called the STEAL study, did and found no correlation, according to Dr. Cotter. "However, when you look at our medians [for biomarker levels] plotted over time, the changes really weren’t maximal until at least 24 weeks, so we would need to have looked at changes up until at least 24 weeks to see if they correlated," she added.

Another attendee, Dr. Michael Yin of Columbia University Medical Center in New York, asked, "Are there plans to follow up with another DXA at a later date, because this is quite similar to the loss that you experience with initiation of ART, although in a different setting. It would be interesting to see whether or not the bone loss continues." Additionally, he wondered if the investigators were looking at other biomarkers.

"There are no plans that I know of to repeat DXA scans on these subjects or to increase the duration of follow-up," Dr. Cotter replied. "We do, however, have samples left and are currently performing vitamin D and parathyroid hormone analysis."

Adult HIV-positive patients were eligible for the PREPARE trial if they had been on a zidovudine-lamivudine–containing regimen as their first treatment for more than 2 years and had had a viral load of fewer than 50 copies of HIV RNA/mL for more than 6 months.

They had a median age of about 46 years, and the majority were male and white. They had been on zidovudine and lamivudine (brand names Retrovir and Epivir) for a median of roughly 5.5 years.

Results showed that compared with the group that continued on zidovudine-lamivudine, the group that switched to tenofovir plus emtricitabine (brand names Viread and Emtriva) had greater changes between baseline and week 48 in three biomarkers of bone turnover: type 1 collagen cross-linked C-telopeptide (P = .0005), osteocalcin (P less than .0001), and procollagen type 1 N-terminal propeptide (P less than .0001).

BMD of the lumbar spine fell by 2.04% from baseline in the group that switched (P = .01) but changed little in the group that continued on the original regimen, resulting in a significant difference between them (P = .03). Neither group had a significant change from baseline in BMD of the femoral neck.

The changes in levels of osteocalcin and procollagen type 1 N-terminal propeptide over the 48-week period were significantly inversely correlated with loss of BMD in the lumbar spine.

In a multivariate analysis adjusted for baseline biomarker level, sex, and ethnicity, the switch from zidovudine-lamivudine to tenofovir-emtricitabine was a significant independent predictor of changes in levels of all three biomarkers.

Among various study limitations, Dr. Cotter acknowledged, was "an absence of data on some classical risk factors, such as smoking and significant use of steroids." Also, "our follow-up was limited to 48 weeks; it would have been interesting to see what happened beyond that," she commented.

Dr. Cotter disclosed no relevant conflicts of interest. The PREPARE trial was supported by an unrestricted scientific grant from Gilead Sciences.

SEATTLE – Elevated blood pressure may warrant more aggressive management in HIV-positive individuals, suggest results from a cohort study reported at the Conference on Retroviruses and Opportunistic Infections.

In addition, the findings suggest that "we also need to address prehypertension, because we saw an increased risk of AMI [acute myocardial infarction] among prehypertensive people," said Kaku Armah, a doctoral student with the University of Pittsburgh’s Graduate School of Public Health.

"Prehypertension is treated with lifestyle modifications in uninfected people, and we think that should also be used in HIV-infected people," he advised.

He and his colleagues studied 82,490 veterans included in the Veterans Aging Cohort Study–Virtual Cohort, identified HIV-positive patients, and then matched each for age, sex, race/ethnicity, and clinical site to two HIV-negative patients. Blood pressures from the three most recent outpatient visits were averaged to obtain a baseline blood pressure.

All the veterans were free of cardiovascular disease at baseline. During a median 4.6-year follow-up, 443 of them had a fatal or nonfatal acute myocardial infarction (AMI).

Initial analyses showed that within each systolic and diastolic blood pressure bracket, the rate of AMI was consistently higher for the HIV-positive patients than for the HIV-negative patients, although there was some overlap of 95% confidence intervals, Mr. Armah reported.

A first multivariate analysis (adjusted for lipids, smoking, body mass index, comorbidities, and other potential confounders) considered systolic blood pressure, using HIV-negative patients having a value of less than 120 mm Hg and not taking any blood pressure medication as the reference group.

Compared with that group, HIV-positive patients had a significantly elevated risk of AMI if they had a systolic blood pressure of 120-139 mm Hg (prehypertension) and were not taking any medication (hazard ratio, 1.7); had a systolic blood pressure of less than 140 mm Hg and were taking medication (HR, 2.2); or had a systolic blood pressure of 140 mm Hg or greater regardless of medication use (HR, 2.4).

Among HIV-negative patients, the corresponding elevations of AMI risk in these categories were smaller; moreover, the elevated risk was significant only in the group having a systolic blood pressure of 140 mm Hg or greater regardless of medication use (HR, 1.6).

In light of these findings, recommendations for the general population to reduce blood pressure below 140/90 mm Hg may not be sufficient for HIV-positive patients, said Dr. Christopher Nguyen, an internist with the Tom Waddell Health Center in San Francisco. Perhaps HIV-positive patients need to be aiming for targets similar to those used for renal or diabetic patients whose target blood pressure is below 130/80 mm Hg.

The findings were much the same in a second multivariate analysis that instead evaluated AMI risk according to diastolic blood pressure categories.

Mr. Armah said that since the findings are observational, there is not enough evidence yet to recommend such a change in practice.

Session comoderator Caroline Sabin, Ph.D., of University College London inquired about the potential role of antiretroviral therapy, because it has been associated with hypertension and elevated MI rates.

Mr. Armah noted that because the study models included both HIV-positive and HIV-negative patients, it was not possible to adjust for antiretroviral therapy, "but we may do a subset analysis looking at just the HIV-infected people."

In addition, analyses have not yet been done to look at the role of inflammatory markers or the severity of HIV infection in the observed associations.

Mr. Armah reported having no relevant conflicts of interest.

SEATTLE – Elevated blood pressure may warrant more aggressive management in HIV-positive individuals, suggest results from a cohort study reported at the Conference on Retroviruses and Opportunistic Infections.

In addition, the findings suggest that "we also need to address prehypertension, because we saw an increased risk of AMI [acute myocardial infarction] among prehypertensive people," said Kaku Armah, a doctoral student with the University of Pittsburgh’s Graduate School of Public Health.

"Prehypertension is treated with lifestyle modifications in uninfected people, and we think that should also be used in HIV-infected people," he advised.

He and his colleagues studied 82,490 veterans included in the Veterans Aging Cohort Study–Virtual Cohort, identified HIV-positive patients, and then matched each for age, sex, race/ethnicity, and clinical site to two HIV-negative patients. Blood pressures from the three most recent outpatient visits were averaged to obtain a baseline blood pressure.

All the veterans were free of cardiovascular disease at baseline. During a median 4.6-year follow-up, 443 of them had a fatal or nonfatal acute myocardial infarction (AMI).

Initial analyses showed that within each systolic and diastolic blood pressure bracket, the rate of AMI was consistently higher for the HIV-positive patients than for the HIV-negative patients, although there was some overlap of 95% confidence intervals, Mr. Armah reported.

A first multivariate analysis (adjusted for lipids, smoking, body mass index, comorbidities, and other potential confounders) considered systolic blood pressure, using HIV-negative patients having a value of less than 120 mm Hg and not taking any blood pressure medication as the reference group.

Compared with that group, HIV-positive patients had a significantly elevated risk of AMI if they had a systolic blood pressure of 120-139 mm Hg (prehypertension) and were not taking any medication (hazard ratio, 1.7); had a systolic blood pressure of less than 140 mm Hg and were taking medication (HR, 2.2); or had a systolic blood pressure of 140 mm Hg or greater regardless of medication use (HR, 2.4).

Among HIV-negative patients, the corresponding elevations of AMI risk in these categories were smaller; moreover, the elevated risk was significant only in the group having a systolic blood pressure of 140 mm Hg or greater regardless of medication use (HR, 1.6).

In light of these findings, recommendations for the general population to reduce blood pressure below 140/90 mm Hg may not be sufficient for HIV-positive patients, said Dr. Christopher Nguyen, an internist with the Tom Waddell Health Center in San Francisco. Perhaps HIV-positive patients need to be aiming for targets similar to those used for renal or diabetic patients whose target blood pressure is below 130/80 mm Hg.

The findings were much the same in a second multivariate analysis that instead evaluated AMI risk according to diastolic blood pressure categories.

Mr. Armah said that since the findings are observational, there is not enough evidence yet to recommend such a change in practice.

Session comoderator Caroline Sabin, Ph.D., of University College London inquired about the potential role of antiretroviral therapy, because it has been associated with hypertension and elevated MI rates.

Mr. Armah noted that because the study models included both HIV-positive and HIV-negative patients, it was not possible to adjust for antiretroviral therapy, "but we may do a subset analysis looking at just the HIV-infected people."

In addition, analyses have not yet been done to look at the role of inflammatory markers or the severity of HIV infection in the observed associations.

Mr. Armah reported having no relevant conflicts of interest.

SEATTLE – Elevated blood pressure may warrant more aggressive management in HIV-positive individuals, suggest results from a cohort study reported at the Conference on Retroviruses and Opportunistic Infections.

In addition, the findings suggest that "we also need to address prehypertension, because we saw an increased risk of AMI [acute myocardial infarction] among prehypertensive people," said Kaku Armah, a doctoral student with the University of Pittsburgh’s Graduate School of Public Health.

"Prehypertension is treated with lifestyle modifications in uninfected people, and we think that should also be used in HIV-infected people," he advised.

He and his colleagues studied 82,490 veterans included in the Veterans Aging Cohort Study–Virtual Cohort, identified HIV-positive patients, and then matched each for age, sex, race/ethnicity, and clinical site to two HIV-negative patients. Blood pressures from the three most recent outpatient visits were averaged to obtain a baseline blood pressure.

All the veterans were free of cardiovascular disease at baseline. During a median 4.6-year follow-up, 443 of them had a fatal or nonfatal acute myocardial infarction (AMI).

Initial analyses showed that within each systolic and diastolic blood pressure bracket, the rate of AMI was consistently higher for the HIV-positive patients than for the HIV-negative patients, although there was some overlap of 95% confidence intervals, Mr. Armah reported.

A first multivariate analysis (adjusted for lipids, smoking, body mass index, comorbidities, and other potential confounders) considered systolic blood pressure, using HIV-negative patients having a value of less than 120 mm Hg and not taking any blood pressure medication as the reference group.

Compared with that group, HIV-positive patients had a significantly elevated risk of AMI if they had a systolic blood pressure of 120-139 mm Hg (prehypertension) and were not taking any medication (hazard ratio, 1.7); had a systolic blood pressure of less than 140 mm Hg and were taking medication (HR, 2.2); or had a systolic blood pressure of 140 mm Hg or greater regardless of medication use (HR, 2.4).

Among HIV-negative patients, the corresponding elevations of AMI risk in these categories were smaller; moreover, the elevated risk was significant only in the group having a systolic blood pressure of 140 mm Hg or greater regardless of medication use (HR, 1.6).

In light of these findings, recommendations for the general population to reduce blood pressure below 140/90 mm Hg may not be sufficient for HIV-positive patients, said Dr. Christopher Nguyen, an internist with the Tom Waddell Health Center in San Francisco. Perhaps HIV-positive patients need to be aiming for targets similar to those used for renal or diabetic patients whose target blood pressure is below 130/80 mm Hg.

The findings were much the same in a second multivariate analysis that instead evaluated AMI risk according to diastolic blood pressure categories.

Mr. Armah said that since the findings are observational, there is not enough evidence yet to recommend such a change in practice.

Session comoderator Caroline Sabin, Ph.D., of University College London inquired about the potential role of antiretroviral therapy, because it has been associated with hypertension and elevated MI rates.

Mr. Armah noted that because the study models included both HIV-positive and HIV-negative patients, it was not possible to adjust for antiretroviral therapy, "but we may do a subset analysis looking at just the HIV-infected people."

In addition, analyses have not yet been done to look at the role of inflammatory markers or the severity of HIV infection in the observed associations.

Mr. Armah reported having no relevant conflicts of interest.

SEATTLE – Treatment with the antidiabetic drug metformin halted the progression of coronary artery calcification in HIV-positive patients who had metabolic syndrome in a randomized clinical trial.

Lifestyle modification had a smaller, nonsignificant benefit, slowing down the progression of coronary artery calcification (CAC), according to the results of the 1-year trial, which enrolled 50 adult patients, Kathleen Fitch reported at the Conference on Retroviruses and Opportunistic Infections.

After 1 year of treatment, CAC scores had increased by 43 points with placebo, by 19 points with lifestyle modification alone, and by 1 point with metformin alone, and had decreased by 4 points with the combination of metformin and lifestyle modification (P = .03 for trend across groups).

Both interventions were well tolerated, and each had some additional benefits, said Ms. Fitch of the Program in Nutritional Metabolism at Massachusetts General Hospital, Boston. For example, metformin reduced insulin resistance, and lifestyle modification improved high-density lipoprotein cholesterol levels, fat content of muscle, C-reactive protein levels, and measures of physical fitness.

"Modification of risk factors for CVD [cardiovascular disease] is important in the management of HIV infection, including strategies for insulin resistance. Metformin may be a useful drug to modify CVD risk," she commented. "A larger study may be required to show lifestyle modification’s effect on CAC."

The study not only showed that metformin had a preventive effect on CAC progression, but also provided a window on the natural history of CAC progression over 1 year in these HIV-infected patients with metabolic syndrome, she said. In fact, the rate of progression seen in the placebo group was about twice the rate that has been reported for the general population.

To put the findings into clinical context, the investigators calculated adjusted Framingham risk scores for a hypothetical patient representative of their study population. At baseline, he had a 10-year risk of CVD events (12%) putting him at intermediate risk, but after a year with no intervention and the expected increase in CAC score, his risk more than doubled (25%), now putting him at high risk. "Importantly, this change would be preventable by metformin since we observed no progression of CAC among those taking metformin," Ms. Fitch said.

Dr. Jens Lundgren of the University of Copenhagen noted that the study may have been limited by the fact that only about half of patients had detectable CAC at baseline, reducing the population that could benefit. "So if you screened for CAC at baseline, would that optimize your power?" he asked.

"Initially, we weren’t sure if every patient would have detectable CAC. We also would hope that metformin would prevent development of CAC in these subjects," Ms. Fitch replied; however, it is possible that subsequent studies might include only patients having detectable CAC.

Dr. James Stein of the University of Wisconsin, Madison, said it was a "great study," but he questioned the possible impact of an imbalance in patients having detectable CAC at baseline, noting that "the single biggest predictor of CAC progression is the presence of CAC to begin with." He recommended repeating the analysis, taking that factor into account. "In the context of many other things that have been looked at for calcium progression, it’s a surprise to see such a change in such a small study," he added.

HIV-positive patients were eligible for the trial if they were 18-65 years old, had been on a stable treatment regimen for more than 6 months, and met criteria for metabolic syndrome but did not have diabetes. "Very few established treatment options exist for this population," Ms. Fitch said.

They were randomized nearly equally to four groups treated on a double-blind basis: placebo with and without lifestyle modification, and metformin with and without lifestyle modification.

Lifestyle modification consisted of 60 minutes three times weekly of cardiovascular and strength training, plus weekly nutrition counseling. Metformin (Glucophage and others) was given at a dose of 500 mg twice daily for 3 months, and then 850 mg twice daily thereafter. CAC was assessed with computed tomography.

The patients’ average age was about 47 years, and 76% were men. The majority were already taking antihypertensive and lipid-lowering medications. Overall, 44% had detectable CAC at baseline.

The four groups had similar rates of treatment discontinuation and similarly high rates of treatment compliance, Ms. Fitch reported. Both interventions were well tolerated: There were six cases of gastrointestinal adverse effects with metformin and two cases of muscle strain with the lifestyle modification.

"Further studies are clearly needed to understand the mechanisms of metformin to prevent CAC progression," she concluded. "And larger, longer-term studies using metformin in HIV-infected patients with metabolic syndrome and insulin resistance will be useful to determine whether this strategy will prevent CVD events."

Ms. Fitch disclosed that she had no relevant conflicts of interest.

SEATTLE – Treatment with the antidiabetic drug metformin halted the progression of coronary artery calcification in HIV-positive patients who had metabolic syndrome in a randomized clinical trial.

Lifestyle modification had a smaller, nonsignificant benefit, slowing down the progression of coronary artery calcification (CAC), according to the results of the 1-year trial, which enrolled 50 adult patients, Kathleen Fitch reported at the Conference on Retroviruses and Opportunistic Infections.

After 1 year of treatment, CAC scores had increased by 43 points with placebo, by 19 points with lifestyle modification alone, and by 1 point with metformin alone, and had decreased by 4 points with the combination of metformin and lifestyle modification (P = .03 for trend across groups).

Both interventions were well tolerated, and each had some additional benefits, said Ms. Fitch of the Program in Nutritional Metabolism at Massachusetts General Hospital, Boston. For example, metformin reduced insulin resistance, and lifestyle modification improved high-density lipoprotein cholesterol levels, fat content of muscle, C-reactive protein levels, and measures of physical fitness.

"Modification of risk factors for CVD [cardiovascular disease] is important in the management of HIV infection, including strategies for insulin resistance. Metformin may be a useful drug to modify CVD risk," she commented. "A larger study may be required to show lifestyle modification’s effect on CAC."

The study not only showed that metformin had a preventive effect on CAC progression, but also provided a window on the natural history of CAC progression over 1 year in these HIV-infected patients with metabolic syndrome, she said. In fact, the rate of progression seen in the placebo group was about twice the rate that has been reported for the general population.

To put the findings into clinical context, the investigators calculated adjusted Framingham risk scores for a hypothetical patient representative of their study population. At baseline, he had a 10-year risk of CVD events (12%) putting him at intermediate risk, but after a year with no intervention and the expected increase in CAC score, his risk more than doubled (25%), now putting him at high risk. "Importantly, this change would be preventable by metformin since we observed no progression of CAC among those taking metformin," Ms. Fitch said.

Dr. Jens Lundgren of the University of Copenhagen noted that the study may have been limited by the fact that only about half of patients had detectable CAC at baseline, reducing the population that could benefit. "So if you screened for CAC at baseline, would that optimize your power?" he asked.

"Initially, we weren’t sure if every patient would have detectable CAC. We also would hope that metformin would prevent development of CAC in these subjects," Ms. Fitch replied; however, it is possible that subsequent studies might include only patients having detectable CAC.

Dr. James Stein of the University of Wisconsin, Madison, said it was a "great study," but he questioned the possible impact of an imbalance in patients having detectable CAC at baseline, noting that "the single biggest predictor of CAC progression is the presence of CAC to begin with." He recommended repeating the analysis, taking that factor into account. "In the context of many other things that have been looked at for calcium progression, it’s a surprise to see such a change in such a small study," he added.

HIV-positive patients were eligible for the trial if they were 18-65 years old, had been on a stable treatment regimen for more than 6 months, and met criteria for metabolic syndrome but did not have diabetes. "Very few established treatment options exist for this population," Ms. Fitch said.

They were randomized nearly equally to four groups treated on a double-blind basis: placebo with and without lifestyle modification, and metformin with and without lifestyle modification.

Lifestyle modification consisted of 60 minutes three times weekly of cardiovascular and strength training, plus weekly nutrition counseling. Metformin (Glucophage and others) was given at a dose of 500 mg twice daily for 3 months, and then 850 mg twice daily thereafter. CAC was assessed with computed tomography.

The patients’ average age was about 47 years, and 76% were men. The majority were already taking antihypertensive and lipid-lowering medications. Overall, 44% had detectable CAC at baseline.

The four groups had similar rates of treatment discontinuation and similarly high rates of treatment compliance, Ms. Fitch reported. Both interventions were well tolerated: There were six cases of gastrointestinal adverse effects with metformin and two cases of muscle strain with the lifestyle modification.

"Further studies are clearly needed to understand the mechanisms of metformin to prevent CAC progression," she concluded. "And larger, longer-term studies using metformin in HIV-infected patients with metabolic syndrome and insulin resistance will be useful to determine whether this strategy will prevent CVD events."

Ms. Fitch disclosed that she had no relevant conflicts of interest.

SEATTLE – Treatment with the antidiabetic drug metformin halted the progression of coronary artery calcification in HIV-positive patients who had metabolic syndrome in a randomized clinical trial.

Lifestyle modification had a smaller, nonsignificant benefit, slowing down the progression of coronary artery calcification (CAC), according to the results of the 1-year trial, which enrolled 50 adult patients, Kathleen Fitch reported at the Conference on Retroviruses and Opportunistic Infections.

After 1 year of treatment, CAC scores had increased by 43 points with placebo, by 19 points with lifestyle modification alone, and by 1 point with metformin alone, and had decreased by 4 points with the combination of metformin and lifestyle modification (P = .03 for trend across groups).

Both interventions were well tolerated, and each had some additional benefits, said Ms. Fitch of the Program in Nutritional Metabolism at Massachusetts General Hospital, Boston. For example, metformin reduced insulin resistance, and lifestyle modification improved high-density lipoprotein cholesterol levels, fat content of muscle, C-reactive protein levels, and measures of physical fitness.

"Modification of risk factors for CVD [cardiovascular disease] is important in the management of HIV infection, including strategies for insulin resistance. Metformin may be a useful drug to modify CVD risk," she commented. "A larger study may be required to show lifestyle modification’s effect on CAC."

The study not only showed that metformin had a preventive effect on CAC progression, but also provided a window on the natural history of CAC progression over 1 year in these HIV-infected patients with metabolic syndrome, she said. In fact, the rate of progression seen in the placebo group was about twice the rate that has been reported for the general population.

To put the findings into clinical context, the investigators calculated adjusted Framingham risk scores for a hypothetical patient representative of their study population. At baseline, he had a 10-year risk of CVD events (12%) putting him at intermediate risk, but after a year with no intervention and the expected increase in CAC score, his risk more than doubled (25%), now putting him at high risk. "Importantly, this change would be preventable by metformin since we observed no progression of CAC among those taking metformin," Ms. Fitch said.

Dr. Jens Lundgren of the University of Copenhagen noted that the study may have been limited by the fact that only about half of patients had detectable CAC at baseline, reducing the population that could benefit. "So if you screened for CAC at baseline, would that optimize your power?" he asked.

"Initially, we weren’t sure if every patient would have detectable CAC. We also would hope that metformin would prevent development of CAC in these subjects," Ms. Fitch replied; however, it is possible that subsequent studies might include only patients having detectable CAC.

Dr. James Stein of the University of Wisconsin, Madison, said it was a "great study," but he questioned the possible impact of an imbalance in patients having detectable CAC at baseline, noting that "the single biggest predictor of CAC progression is the presence of CAC to begin with." He recommended repeating the analysis, taking that factor into account. "In the context of many other things that have been looked at for calcium progression, it’s a surprise to see such a change in such a small study," he added.

HIV-positive patients were eligible for the trial if they were 18-65 years old, had been on a stable treatment regimen for more than 6 months, and met criteria for metabolic syndrome but did not have diabetes. "Very few established treatment options exist for this population," Ms. Fitch said.

They were randomized nearly equally to four groups treated on a double-blind basis: placebo with and without lifestyle modification, and metformin with and without lifestyle modification.

Lifestyle modification consisted of 60 minutes three times weekly of cardiovascular and strength training, plus weekly nutrition counseling. Metformin (Glucophage and others) was given at a dose of 500 mg twice daily for 3 months, and then 850 mg twice daily thereafter. CAC was assessed with computed tomography.

The patients’ average age was about 47 years, and 76% were men. The majority were already taking antihypertensive and lipid-lowering medications. Overall, 44% had detectable CAC at baseline.

The four groups had similar rates of treatment discontinuation and similarly high rates of treatment compliance, Ms. Fitch reported. Both interventions were well tolerated: There were six cases of gastrointestinal adverse effects with metformin and two cases of muscle strain with the lifestyle modification.

"Further studies are clearly needed to understand the mechanisms of metformin to prevent CAC progression," she concluded. "And larger, longer-term studies using metformin in HIV-infected patients with metabolic syndrome and insulin resistance will be useful to determine whether this strategy will prevent CVD events."

Ms. Fitch disclosed that she had no relevant conflicts of interest.

SEATTLE – Greater efforts are needed to get people with HIV infection into medical care, a necessary prerequisite to therapy and viral suppression, suggests a cross-sectional survey of 4,217 HIV-positive adults conducted by the Centers for Disease Control and Prevention.

Survey results, reported at the Conference on Retroviruses and Opportunistic Infections, also showed that only an estimated 36% of adults living with HIV in 2009 had at least one medical care visit between January and April of that year.

© Dr. A. Harrison; Dr. P. Feorino / CDC

But within this group, measures of therapy were good: 89% had received at least one prescription for antiretroviral therapy (ART) in the past year, and 72% had achieved a suppressed HIV viral load, defined as having 200 copies/mL or less of the virus at the most recent measurement in the past year.

"Increasing the size of the in-care population is critical to increase the overall proportion of HIV-infected persons who are on ART and suppressed," said Dr. Jacek Skarbinski, an investigator in the Division of HIV/AIDS Prevention at the CDC. "We find that most HIV-infected adults in care are already on ART."

Analyses have suggested that expanding guidelines regarding when to initiate ART – from the current recommendation (presence of AIDS or a nadir CD4 cell count of 500 cells/mL or lower) to a new one covering all HIV-infected people (regardless of CD4 cell count) – would have only a small impact. Such expansion would increase the percentage of people in care who are on ART by just 3%.

In additional study findings, certain groups of people in care – young adults, blacks, and those living in poverty, among others – were significantly less likely to be prescribed ART, to achieve viral suppression, or both. Thus, "we need to address disparities in HIV care and treatment, especially by age, race, and income," Dr. Skarbinski maintained.

"The study is interesting as it highlights what can be achieved through use of basic epidemiological tools to provide estimates of the numbers receiving treatment across the country as a whole and within subgroups," Kholoud Porter, Ph.D., session comoderator and senior epidemiologist with the MRC Clinical Trials Unit in London, said in an interview. "This is important information for health care planning."

"The continuum of engagement in HIV care includes HIV diagnosis, linkage to and retention in care, prescription of ART, and viral suppression," Dr. Skarbinski said.

To obtain national estimates of these outcomes, he and colleagues analyzed data from the Medical Monitoring Project, a supplemental surveillance system that captures information on nationally representative samples of HIV-infected people in care.

In 2009, it collected data from 17 states and territories, 461 facilities within those states and territories, and 4,217 HIV-infected patients receiving care in those facilities. Patients were interviewed and their medical records were abstracted to ascertain prescription of ART and achievement of viral suppression.

The patients represented an estimated 421,186 adults in care at the population level, or just 36% of all 1.2 million people living with HIV nationally on the basis of a recent estimate (MMWR Morb. Mortal. Wkly. Rep. 2011;60:689-93). The value was higher, but still only 41%, when analyses were annualized to reflect receipt of care during the whole year and not just the first 4 months.

Patients in care were predominantly 40 years of age or older (75%), male (71%), non-Hispanic black (41%) or white (34%), and men who had sex with men (47%). The majority had more than a high school education (51%) but also lived below the poverty line (54%) and had public health insurance (62%). Half were at least 10 years out from diagnosis, and two-thirds had AIDS.

Multivariate analyses showed that individuals in care were significantly less likely to be prescribed ART if they were aged 18-29, non-Hispanic black, female, in the first 4 years after diagnosis, and did not have AIDS (regardless of nadir CD4 cell count).

Similarly, individuals in care were significantly less likely to be prescribed antiretroviral therapy if they were aged 18-49, non-Hispanic black or of "other" race/ethnicity, were living at or below the poverty level, and did not have AIDS and had a nadir CD4 cell count of greater than 500.

The study data suggested that nationally, 45,133 HIV-infected adults in care were not prescribed ART, of whom 74% were eligible under current treatment guidelines.

Dr. Skarbinski disclosed that he had no relevant conflicts of interest.

SEATTLE – Greater efforts are needed to get people with HIV infection into medical care, a necessary prerequisite to therapy and viral suppression, suggests a cross-sectional survey of 4,217 HIV-positive adults conducted by the Centers for Disease Control and Prevention.

Survey results, reported at the Conference on Retroviruses and Opportunistic Infections, also showed that only an estimated 36% of adults living with HIV in 2009 had at least one medical care visit between January and April of that year.

© Dr. A. Harrison; Dr. P. Feorino / CDC

But within this group, measures of therapy were good: 89% had received at least one prescription for antiretroviral therapy (ART) in the past year, and 72% had achieved a suppressed HIV viral load, defined as having 200 copies/mL or less of the virus at the most recent measurement in the past year.

"Increasing the size of the in-care population is critical to increase the overall proportion of HIV-infected persons who are on ART and suppressed," said Dr. Jacek Skarbinski, an investigator in the Division of HIV/AIDS Prevention at the CDC. "We find that most HIV-infected adults in care are already on ART."

Analyses have suggested that expanding guidelines regarding when to initiate ART – from the current recommendation (presence of AIDS or a nadir CD4 cell count of 500 cells/mL or lower) to a new one covering all HIV-infected people (regardless of CD4 cell count) – would have only a small impact. Such expansion would increase the percentage of people in care who are on ART by just 3%.

In additional study findings, certain groups of people in care – young adults, blacks, and those living in poverty, among others – were significantly less likely to be prescribed ART, to achieve viral suppression, or both. Thus, "we need to address disparities in HIV care and treatment, especially by age, race, and income," Dr. Skarbinski maintained.

"The study is interesting as it highlights what can be achieved through use of basic epidemiological tools to provide estimates of the numbers receiving treatment across the country as a whole and within subgroups," Kholoud Porter, Ph.D., session comoderator and senior epidemiologist with the MRC Clinical Trials Unit in London, said in an interview. "This is important information for health care planning."

"The continuum of engagement in HIV care includes HIV diagnosis, linkage to and retention in care, prescription of ART, and viral suppression," Dr. Skarbinski said.

To obtain national estimates of these outcomes, he and colleagues analyzed data from the Medical Monitoring Project, a supplemental surveillance system that captures information on nationally representative samples of HIV-infected people in care.

In 2009, it collected data from 17 states and territories, 461 facilities within those states and territories, and 4,217 HIV-infected patients receiving care in those facilities. Patients were interviewed and their medical records were abstracted to ascertain prescription of ART and achievement of viral suppression.

The patients represented an estimated 421,186 adults in care at the population level, or just 36% of all 1.2 million people living with HIV nationally on the basis of a recent estimate (MMWR Morb. Mortal. Wkly. Rep. 2011;60:689-93). The value was higher, but still only 41%, when analyses were annualized to reflect receipt of care during the whole year and not just the first 4 months.

Patients in care were predominantly 40 years of age or older (75%), male (71%), non-Hispanic black (41%) or white (34%), and men who had sex with men (47%). The majority had more than a high school education (51%) but also lived below the poverty line (54%) and had public health insurance (62%). Half were at least 10 years out from diagnosis, and two-thirds had AIDS.

Multivariate analyses showed that individuals in care were significantly less likely to be prescribed ART if they were aged 18-29, non-Hispanic black, female, in the first 4 years after diagnosis, and did not have AIDS (regardless of nadir CD4 cell count).

Similarly, individuals in care were significantly less likely to be prescribed antiretroviral therapy if they were aged 18-49, non-Hispanic black or of "other" race/ethnicity, were living at or below the poverty level, and did not have AIDS and had a nadir CD4 cell count of greater than 500.

The study data suggested that nationally, 45,133 HIV-infected adults in care were not prescribed ART, of whom 74% were eligible under current treatment guidelines.

Dr. Skarbinski disclosed that he had no relevant conflicts of interest.

SEATTLE – Greater efforts are needed to get people with HIV infection into medical care, a necessary prerequisite to therapy and viral suppression, suggests a cross-sectional survey of 4,217 HIV-positive adults conducted by the Centers for Disease Control and Prevention.

Survey results, reported at the Conference on Retroviruses and Opportunistic Infections, also showed that only an estimated 36% of adults living with HIV in 2009 had at least one medical care visit between January and April of that year.

© Dr. A. Harrison; Dr. P. Feorino / CDC

But within this group, measures of therapy were good: 89% had received at least one prescription for antiretroviral therapy (ART) in the past year, and 72% had achieved a suppressed HIV viral load, defined as having 200 copies/mL or less of the virus at the most recent measurement in the past year.

"Increasing the size of the in-care population is critical to increase the overall proportion of HIV-infected persons who are on ART and suppressed," said Dr. Jacek Skarbinski, an investigator in the Division of HIV/AIDS Prevention at the CDC. "We find that most HIV-infected adults in care are already on ART."

Analyses have suggested that expanding guidelines regarding when to initiate ART – from the current recommendation (presence of AIDS or a nadir CD4 cell count of 500 cells/mL or lower) to a new one covering all HIV-infected people (regardless of CD4 cell count) – would have only a small impact. Such expansion would increase the percentage of people in care who are on ART by just 3%.

In additional study findings, certain groups of people in care – young adults, blacks, and those living in poverty, among others – were significantly less likely to be prescribed ART, to achieve viral suppression, or both. Thus, "we need to address disparities in HIV care and treatment, especially by age, race, and income," Dr. Skarbinski maintained.

"The study is interesting as it highlights what can be achieved through use of basic epidemiological tools to provide estimates of the numbers receiving treatment across the country as a whole and within subgroups," Kholoud Porter, Ph.D., session comoderator and senior epidemiologist with the MRC Clinical Trials Unit in London, said in an interview. "This is important information for health care planning."

"The continuum of engagement in HIV care includes HIV diagnosis, linkage to and retention in care, prescription of ART, and viral suppression," Dr. Skarbinski said.

To obtain national estimates of these outcomes, he and colleagues analyzed data from the Medical Monitoring Project, a supplemental surveillance system that captures information on nationally representative samples of HIV-infected people in care.

In 2009, it collected data from 17 states and territories, 461 facilities within those states and territories, and 4,217 HIV-infected patients receiving care in those facilities. Patients were interviewed and their medical records were abstracted to ascertain prescription of ART and achievement of viral suppression.

The patients represented an estimated 421,186 adults in care at the population level, or just 36% of all 1.2 million people living with HIV nationally on the basis of a recent estimate (MMWR Morb. Mortal. Wkly. Rep. 2011;60:689-93). The value was higher, but still only 41%, when analyses were annualized to reflect receipt of care during the whole year and not just the first 4 months.

Patients in care were predominantly 40 years of age or older (75%), male (71%), non-Hispanic black (41%) or white (34%), and men who had sex with men (47%). The majority had more than a high school education (51%) but also lived below the poverty line (54%) and had public health insurance (62%). Half were at least 10 years out from diagnosis, and two-thirds had AIDS.

Multivariate analyses showed that individuals in care were significantly less likely to be prescribed ART if they were aged 18-29, non-Hispanic black, female, in the first 4 years after diagnosis, and did not have AIDS (regardless of nadir CD4 cell count).

Similarly, individuals in care were significantly less likely to be prescribed antiretroviral therapy if they were aged 18-49, non-Hispanic black or of "other" race/ethnicity, were living at or below the poverty level, and did not have AIDS and had a nadir CD4 cell count of greater than 500.

The study data suggested that nationally, 45,133 HIV-infected adults in care were not prescribed ART, of whom 74% were eligible under current treatment guidelines.

Dr. Skarbinski disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at the meeting.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said at a meeting on gastrointestinal cancer sponosored by the American Society of Clinical Oncology.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior.

"Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented.

"Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview.

"The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and from trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer.

"I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant financial conflicts of interest.

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at the meeting.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said at a meeting on gastrointestinal cancer sponosored by the American Society of Clinical Oncology.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior.

"Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented.

"Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview.

"The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and from trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer.

"I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant financial conflicts of interest.

SAN FRANCISCO – A new 86-gene signature may add to metabolic imaging in guiding early treatment decisions for esophagogastric junction cancer, researchers reported.

The leptin gene, among others, stood out as having the potential to become a clinically useful biomarker in analyses that were presented at the meeting.

Dr. Russell Petty of the University of Aberdeen (Scotland) and colleagues studied 182 patients with locally advanced or metastatic disease. The investigators performed FDG-PET (¹⁸fluorodeoxyglucose–positron emission tomography) imaging and CT imaging, as well as gene expression profiling, and immunohistochemistry of pretreatment tumor tissue.

Results showed that among a subgroup of 14 patients who had a PET metabolic response to the first cycle of neoadjuvant chemotherapy, a set of 86 genes in pretreatment tumor tissue distinguished those who had a radiologic response on CT after completing all cycles of that chemotherapy, compared with those who did not respond. In a variety of predictive models, this gene signature correctly predicted radiologic response in all cases.

"We have shown that gene expression profiling can subclassify FDG-PET metabolic responders into those patients that will and will not subsequently go on to have a [radiologic] response. We have also shown that combining molecular biomarkers and FDG-PET allows an optimization of response prediction," Dr. Petty said at a meeting on gastrointestinal cancer sponosored by the American Society of Clinical Oncology.

This is key, as PET alone has a poor positive predictive value in this setting, with only half of PET responders to neoadjuvant chemotherapy eventually showing a histopathologic response.

"While I suppose there is little doubt that if we used PET in this way to make treatment decisions, we would have a system that would be better than unstratified empirical treatment, what it still means is that quite significant proportions of our patients will go on to receive ineffective and intensely toxic therapy," he commented.

A subsequent gene enrichment and pathway analysis identified a half-dozen pathways that provided potential mechanistic explanations for the different tumor behavior.

"Within the pathways identified, the adipocytokine-signaling pathway immediately caught our attention because of the strong known [epidemiologic] link between obesity and body weight, and esophagogastric adenocarcinoma," Dr. Petty noted.

Additional analyses specifically fingered the leptin gene (among others) and showed that among PET responders, leptin expression was higher in radiologic nonresponders than in responders (P = .026).

Yet, immunohistochemistry in an independent group of 154 patients showed that strong leptin staining was also associated with better survival (P = .021), an association that held up in multivariate analysis (hazard ratio, 0.85; P = .04).

In stratified analyses, patients with leptin-positive tumors derived little survival benefit from neoadjuvant chemotherapy, whereas those with leptin-negative tumors fared considerably better if they received this therapy (indeed, about as well as the positive group).

"Leptin in particular may be a molecular biomarker that is useful to combine with PET," Dr. Petty commented.

"Leptin expression is associated with chemoresistance, but at the same time is also a favorable therapy-independent biomarker, so this combination of predictive and therapy-independent prognostic impacts mean that leptin has the potential to be a clinically useful biomarker."

"I really think that this is groundbreaking. ... The real future is here" when it comes to predicting treatment response in this cancer, as suggested by this study and others," session cochair Dr. Mark Krasna of the St. Joseph Medical Center in Towson, Md., commented in an interview.

"The question now is, are we ready for prime time to adopt that throughout?"

At present, more research is needed, according to Dr. Krasna, such as the ongoing validation of the 86-gene signature and from trials like CALGB (Cancer and Leukemia Group B) 80803 exploring response-adaptive treatment in this cancer.

"I think those are the important things we can do today. We are ready for that," he concluded.

Dr. Petty and Dr. Krasna reported that they had no relevant financial conflicts of interest.