Diana Mahoney

BOSTON — The incidence of steroid-induced osteonecrosis is significantly lower in childhood systemic lupus erythematosus than in adults with the disease, according to the findings of a prospective MRI study. Additionally, among pediatric patients, age of lupus onset is an independent risk factor for the degenerative bone condition, Dr. Junichi Nakamura reported at the annual meeting of the Pediatric Orthopaedic Society of North America.

Characterized by the death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone, osteonecrosis is a well-known complication of systemic lupus erythematosus (SLE) and is often associated with steroid therapy, yet the incidence of steroid-induced osteonecrosis in childhood SLE has not been well established, according to Dr. Nakamura of Chiba (Japan) Children's Hospital.

To assess the relative incidence of the condition in children and adults and to determine associated risk factors in children, Dr. Nakamura and his colleagues prospectively studied 169 patients, including 43 with childhood lupus (aged younger than 20 years at time of diagnosis) and 126 adults with the disease. All the patients fulfilled the 1982 revised American College of Rheumatology criteria for SLE, and all underwent MRI of the knee and hip when steroid therapy was initiated and again after at least 1 year of steroid therapy. The mean follow-up period was 7.8 years, and the follow-up rate was 100%, he said.

In total, 676 joint MRIs were analyzed, including initial and follow-up knee and hip MRIs for each adult and childhood SLE patient, Dr. Nakamura said. “The incidence of osteonecrosis was significantly lower in the childhood SLE group than the adults [31% and 41%, respectively].” During the follow-up period, osteonecrosis developed in 20 hips and 33 knees of 20 childhood SLE patients, and in 95 hips and 112 knees of 74 adult SLE patients, he reported.

Among the childhood SLE patients, age at SLE onset, highest dose of corticosteroid per day, and highest dose of corticosteroid per weight per day were compared between those who did and did not develop osteonecrosis, Dr. Nakamura said. The mean age of SLE onset in the osteonecrosis group was 17.2 years, compared with 13.3 years in the nonosteonecrosis group, representing a significant difference. The highest corticosteroid dose per day and the highest dose per weight per day were statistically similar between the two groups, he said.

In logistic regression analysis, “the incidence of osteonecrosis was significantly lower at the younger age of initial steroid treatment,” said Dr. Nakamura. “The odds ratio for osteonecrosis associated with older age of onset was 1.31.” Dosage was not a risk factor, he said.

In the childhood SLE group, “osteonecrosis never developed before 14 years of age,” said Dr. Nakamura. “The youngest patients with osteonecrosis included a 14.9-year-old with osteonecrosis in the hip and a 15.5-year-old with osteonecrosis in the knee.”

Although the findings should be replicated in a larger investigation, clinicians should be cognizant of the potential increased risk of osteonecrosis in children diagnosed with SLE at a later age, in order to optimize screening and management, Dr. Nakamura concluded.

Dr. Nakamura had no conflicts of interest to disclose with respect to his presentation.

T1 MRI of a 17-year-old girl on steroids shows femoral head osteonecrosis.

STIR shows bone marrow edema, right femoral head collapse 10 years later.

Patient had intertrochanteric curved varus osteotomy of Nishio on right hip.

Collapse of bilateral femoral head had not progressed 9 years after surgery.

T1 (left) and STIR MRI (right) show osteonecrosis of the femoral head in a 15-year-old with SLE. The growth plates of the femoral heads have already closed. Images courtesy Dr. Junichi Nakamura

MRI shows reduction of femoral head osteonecrosis 19 years after steroids.

BOSTON — The incidence of steroid-induced osteonecrosis is significantly lower in childhood systemic lupus erythematosus than in adults with the disease, according to the findings of a prospective MRI study. Additionally, among pediatric patients, age of lupus onset is an independent risk factor for the degenerative bone condition, Dr. Junichi Nakamura reported at the annual meeting of the Pediatric Orthopaedic Society of North America.

Characterized by the death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone, osteonecrosis is a well-known complication of systemic lupus erythematosus (SLE) and is often associated with steroid therapy, yet the incidence of steroid-induced osteonecrosis in childhood SLE has not been well established, according to Dr. Nakamura of Chiba (Japan) Children's Hospital.

To assess the relative incidence of the condition in children and adults and to determine associated risk factors in children, Dr. Nakamura and his colleagues prospectively studied 169 patients, including 43 with childhood lupus (aged younger than 20 years at time of diagnosis) and 126 adults with the disease. All the patients fulfilled the 1982 revised American College of Rheumatology criteria for SLE, and all underwent MRI of the knee and hip when steroid therapy was initiated and again after at least 1 year of steroid therapy. The mean follow-up period was 7.8 years, and the follow-up rate was 100%, he said.

In total, 676 joint MRIs were analyzed, including initial and follow-up knee and hip MRIs for each adult and childhood SLE patient, Dr. Nakamura said. “The incidence of osteonecrosis was significantly lower in the childhood SLE group than the adults [31% and 41%, respectively].” During the follow-up period, osteonecrosis developed in 20 hips and 33 knees of 20 childhood SLE patients, and in 95 hips and 112 knees of 74 adult SLE patients, he reported.

Among the childhood SLE patients, age at SLE onset, highest dose of corticosteroid per day, and highest dose of corticosteroid per weight per day were compared between those who did and did not develop osteonecrosis, Dr. Nakamura said. The mean age of SLE onset in the osteonecrosis group was 17.2 years, compared with 13.3 years in the nonosteonecrosis group, representing a significant difference. The highest corticosteroid dose per day and the highest dose per weight per day were statistically similar between the two groups, he said.

In logistic regression analysis, “the incidence of osteonecrosis was significantly lower at the younger age of initial steroid treatment,” said Dr. Nakamura. “The odds ratio for osteonecrosis associated with older age of onset was 1.31.” Dosage was not a risk factor, he said.

In the childhood SLE group, “osteonecrosis never developed before 14 years of age,” said Dr. Nakamura. “The youngest patients with osteonecrosis included a 14.9-year-old with osteonecrosis in the hip and a 15.5-year-old with osteonecrosis in the knee.”

Although the findings should be replicated in a larger investigation, clinicians should be cognizant of the potential increased risk of osteonecrosis in children diagnosed with SLE at a later age, in order to optimize screening and management, Dr. Nakamura concluded.

Dr. Nakamura had no conflicts of interest to disclose with respect to his presentation.

T1 MRI of a 17-year-old girl on steroids shows femoral head osteonecrosis.

STIR shows bone marrow edema, right femoral head collapse 10 years later.

Patient had intertrochanteric curved varus osteotomy of Nishio on right hip.

Collapse of bilateral femoral head had not progressed 9 years after surgery.

T1 (left) and STIR MRI (right) show osteonecrosis of the femoral head in a 15-year-old with SLE. The growth plates of the femoral heads have already closed. Images courtesy Dr. Junichi Nakamura

MRI shows reduction of femoral head osteonecrosis 19 years after steroids.

BOSTON — The incidence of steroid-induced osteonecrosis is significantly lower in childhood systemic lupus erythematosus than in adults with the disease, according to the findings of a prospective MRI study. Additionally, among pediatric patients, age of lupus onset is an independent risk factor for the degenerative bone condition, Dr. Junichi Nakamura reported at the annual meeting of the Pediatric Orthopaedic Society of North America.

Characterized by the death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone, osteonecrosis is a well-known complication of systemic lupus erythematosus (SLE) and is often associated with steroid therapy, yet the incidence of steroid-induced osteonecrosis in childhood SLE has not been well established, according to Dr. Nakamura of Chiba (Japan) Children's Hospital.

To assess the relative incidence of the condition in children and adults and to determine associated risk factors in children, Dr. Nakamura and his colleagues prospectively studied 169 patients, including 43 with childhood lupus (aged younger than 20 years at time of diagnosis) and 126 adults with the disease. All the patients fulfilled the 1982 revised American College of Rheumatology criteria for SLE, and all underwent MRI of the knee and hip when steroid therapy was initiated and again after at least 1 year of steroid therapy. The mean follow-up period was 7.8 years, and the follow-up rate was 100%, he said.

In total, 676 joint MRIs were analyzed, including initial and follow-up knee and hip MRIs for each adult and childhood SLE patient, Dr. Nakamura said. “The incidence of osteonecrosis was significantly lower in the childhood SLE group than the adults [31% and 41%, respectively].” During the follow-up period, osteonecrosis developed in 20 hips and 33 knees of 20 childhood SLE patients, and in 95 hips and 112 knees of 74 adult SLE patients, he reported.

Among the childhood SLE patients, age at SLE onset, highest dose of corticosteroid per day, and highest dose of corticosteroid per weight per day were compared between those who did and did not develop osteonecrosis, Dr. Nakamura said. The mean age of SLE onset in the osteonecrosis group was 17.2 years, compared with 13.3 years in the nonosteonecrosis group, representing a significant difference. The highest corticosteroid dose per day and the highest dose per weight per day were statistically similar between the two groups, he said.

In logistic regression analysis, “the incidence of osteonecrosis was significantly lower at the younger age of initial steroid treatment,” said Dr. Nakamura. “The odds ratio for osteonecrosis associated with older age of onset was 1.31.” Dosage was not a risk factor, he said.

In the childhood SLE group, “osteonecrosis never developed before 14 years of age,” said Dr. Nakamura. “The youngest patients with osteonecrosis included a 14.9-year-old with osteonecrosis in the hip and a 15.5-year-old with osteonecrosis in the knee.”

Although the findings should be replicated in a larger investigation, clinicians should be cognizant of the potential increased risk of osteonecrosis in children diagnosed with SLE at a later age, in order to optimize screening and management, Dr. Nakamura concluded.

Dr. Nakamura had no conflicts of interest to disclose with respect to his presentation.

T1 MRI of a 17-year-old girl on steroids shows femoral head osteonecrosis.

STIR shows bone marrow edema, right femoral head collapse 10 years later.

Patient had intertrochanteric curved varus osteotomy of Nishio on right hip.

Collapse of bilateral femoral head had not progressed 9 years after surgery.

T1 (left) and STIR MRI (right) show osteonecrosis of the femoral head in a 15-year-old with SLE. The growth plates of the femoral heads have already closed. Images courtesy Dr. Junichi Nakamura

MRI shows reduction of femoral head osteonecrosis 19 years after steroids.

DESTIN, FLA. — A safety and efficacy trial is underway of an agent designed to treat dermatomyositis or polymyositis in adults via the novel approach of blocking interferon-alpha or its receptor.

Dr. Steven A. Greenberg reported that he and his colleagues are currently assessing the safety and tolerability of multidose, intravenously administered MEDI-545 (a fully human anti-interferon-alpha monoclonal antibody) in adult patients with dermatomyositis or polymyositis. The agent is being tested in study MI-CP151, a phase IB clinical trial sponsored by the drug manufacturer, MedImmune Inc.

“This is a true personalized-medicine trial, in that patients have to have a pattern of type I interferon-inducible gene activation in their blood by microarray studies to be enrolled,” said Dr. Greenberg, a neurologist at Brigham and Women's Hospital in Boston. He noted that in a rank-order listing of blood gene expression of patients with active disease who are enrolled in the study thus far, 90% of the genes are type I interferon transcripts, confirming that “these are biomarkers of active disease.”

Microarray and protein studies are identifying long-overlooked immune system cell types and processes that are involved in muscle damage in these diseases; such findings open channels for more targeted drug development and clinical trials of existing drugs that act on these immune pathways.

For example, dermatomyositis is characterized by progressive proximal muscle inflammation and weakness, as well as associated skin changes. “The way people have thought about this disease for a couple of decades is that the muscle injury is an end product of capillary injury,” said Dr. Greenberg at the Congress of Clinical Rheumatology. “It has largely been believed that dermatomyositis is a disease in which antibodies are binding to an endothelial cell antigen, causing complement-mediated injury in capillaries, and that the capillary injury eventually causes ischemia to muscle. According to this model, the characteristic perifascicular atrophy is thought to simply be a result of lack of blood supply to muscle.”

There are a number of problems with this theoretical model, Dr. Greenberg explained. “Importantly, no antigens or antibodies have been demonstrated and, in experimental models of ischemia, perifascicular atrophy doesn't occur. Experimental ischemic myopathy actually affects the central portions of fascicles, not the peripheral portions,” he said. “Nor does one ever see perifascicular atrophy in vasculitis, the one disease in which we do know there is muscular ischemia.”

Plasmacytoid dendritic cells, which produce alpha and beta interferons, have recently been identified in the muscle and skin of patients with dermatomyositis. Gene-expression profiling of these cells shows significant up-regulation of type I interferon-alpha/-beta-inducible genes that correlates with disease activity. These findings suggest a different mechanistic model, said Dr. Greenberg. “One potential way to think about this disease is that the overproduction of type I interferon-usable proteins, regardless of the mechanism, may be separately injuring both capillaries and the perifascicular muscle fibers,” he said.

“There are muscle fibers that appear to be dying for no apparent reason. There are no immunoglobulin molecules; there are no T cells touching them,” said Dr. Greenberg. “The question that arises is whether the production of some interferon-inducible transcript or protein within myofibers themselves could injure the muscle fibers,” he said.

“Is this an autoimmune disease in which tissue injury results from the intracellular proteins of the innate immune system, rather than by-products of the adaptive immune system, either in the immunoglobulin molecules secreted by plasma cells or effector cytotoxic molecules secreted by CD8 plasma T cells?”

Given this possibility, “it is very reasonable to try blocking interferon-alpha or its receptor for the treatment of dermatomyositis,” said Dr. Greenberg. The paradigm for muscle injury in inclusion body myositis (IBM) and polymyositis should also be revisited in light of recent “surprises,” according to Dr. Greenberg. Both diseases have long been considered “classic intramuscular CD8 T-cell-mediated diseases.” However, recent research has demonstrated an abundance of both myeloid dendritic cells (which are implicated in triggering the adaptive immune system) and differentiated B cells (in the form of CD138+ plasma cells) in the inflamed muscle tissue of patients with either IBM or polymyositis.

These findings, taken together, broaden the pool of potential therapeutic agents. “There are at lease 15 [Food and Drug Administration]-approved drugs targeting these molecules of interest,” said Dr. Greenberg.

He disclosed having a sponsored-research agreement with MedImmune for support of his research laboratory, but noted that all data discussed in this presentation were obtained prior to this agreement.

DESTIN, FLA. — A safety and efficacy trial is underway of an agent designed to treat dermatomyositis or polymyositis in adults via the novel approach of blocking interferon-alpha or its receptor.

Dr. Steven A. Greenberg reported that he and his colleagues are currently assessing the safety and tolerability of multidose, intravenously administered MEDI-545 (a fully human anti-interferon-alpha monoclonal antibody) in adult patients with dermatomyositis or polymyositis. The agent is being tested in study MI-CP151, a phase IB clinical trial sponsored by the drug manufacturer, MedImmune Inc.

“This is a true personalized-medicine trial, in that patients have to have a pattern of type I interferon-inducible gene activation in their blood by microarray studies to be enrolled,” said Dr. Greenberg, a neurologist at Brigham and Women's Hospital in Boston. He noted that in a rank-order listing of blood gene expression of patients with active disease who are enrolled in the study thus far, 90% of the genes are type I interferon transcripts, confirming that “these are biomarkers of active disease.”

Microarray and protein studies are identifying long-overlooked immune system cell types and processes that are involved in muscle damage in these diseases; such findings open channels for more targeted drug development and clinical trials of existing drugs that act on these immune pathways.

For example, dermatomyositis is characterized by progressive proximal muscle inflammation and weakness, as well as associated skin changes. “The way people have thought about this disease for a couple of decades is that the muscle injury is an end product of capillary injury,” said Dr. Greenberg at the Congress of Clinical Rheumatology. “It has largely been believed that dermatomyositis is a disease in which antibodies are binding to an endothelial cell antigen, causing complement-mediated injury in capillaries, and that the capillary injury eventually causes ischemia to muscle. According to this model, the characteristic perifascicular atrophy is thought to simply be a result of lack of blood supply to muscle.”

There are a number of problems with this theoretical model, Dr. Greenberg explained. “Importantly, no antigens or antibodies have been demonstrated and, in experimental models of ischemia, perifascicular atrophy doesn't occur. Experimental ischemic myopathy actually affects the central portions of fascicles, not the peripheral portions,” he said. “Nor does one ever see perifascicular atrophy in vasculitis, the one disease in which we do know there is muscular ischemia.”

Plasmacytoid dendritic cells, which produce alpha and beta interferons, have recently been identified in the muscle and skin of patients with dermatomyositis. Gene-expression profiling of these cells shows significant up-regulation of type I interferon-alpha/-beta-inducible genes that correlates with disease activity. These findings suggest a different mechanistic model, said Dr. Greenberg. “One potential way to think about this disease is that the overproduction of type I interferon-usable proteins, regardless of the mechanism, may be separately injuring both capillaries and the perifascicular muscle fibers,” he said.

“There are muscle fibers that appear to be dying for no apparent reason. There are no immunoglobulin molecules; there are no T cells touching them,” said Dr. Greenberg. “The question that arises is whether the production of some interferon-inducible transcript or protein within myofibers themselves could injure the muscle fibers,” he said.

“Is this an autoimmune disease in which tissue injury results from the intracellular proteins of the innate immune system, rather than by-products of the adaptive immune system, either in the immunoglobulin molecules secreted by plasma cells or effector cytotoxic molecules secreted by CD8 plasma T cells?”

Given this possibility, “it is very reasonable to try blocking interferon-alpha or its receptor for the treatment of dermatomyositis,” said Dr. Greenberg. The paradigm for muscle injury in inclusion body myositis (IBM) and polymyositis should also be revisited in light of recent “surprises,” according to Dr. Greenberg. Both diseases have long been considered “classic intramuscular CD8 T-cell-mediated diseases.” However, recent research has demonstrated an abundance of both myeloid dendritic cells (which are implicated in triggering the adaptive immune system) and differentiated B cells (in the form of CD138+ plasma cells) in the inflamed muscle tissue of patients with either IBM or polymyositis.

These findings, taken together, broaden the pool of potential therapeutic agents. “There are at lease 15 [Food and Drug Administration]-approved drugs targeting these molecules of interest,” said Dr. Greenberg.

He disclosed having a sponsored-research agreement with MedImmune for support of his research laboratory, but noted that all data discussed in this presentation were obtained prior to this agreement.

DESTIN, FLA. — A safety and efficacy trial is underway of an agent designed to treat dermatomyositis or polymyositis in adults via the novel approach of blocking interferon-alpha or its receptor.

Dr. Steven A. Greenberg reported that he and his colleagues are currently assessing the safety and tolerability of multidose, intravenously administered MEDI-545 (a fully human anti-interferon-alpha monoclonal antibody) in adult patients with dermatomyositis or polymyositis. The agent is being tested in study MI-CP151, a phase IB clinical trial sponsored by the drug manufacturer, MedImmune Inc.

“This is a true personalized-medicine trial, in that patients have to have a pattern of type I interferon-inducible gene activation in their blood by microarray studies to be enrolled,” said Dr. Greenberg, a neurologist at Brigham and Women's Hospital in Boston. He noted that in a rank-order listing of blood gene expression of patients with active disease who are enrolled in the study thus far, 90% of the genes are type I interferon transcripts, confirming that “these are biomarkers of active disease.”

Microarray and protein studies are identifying long-overlooked immune system cell types and processes that are involved in muscle damage in these diseases; such findings open channels for more targeted drug development and clinical trials of existing drugs that act on these immune pathways.

For example, dermatomyositis is characterized by progressive proximal muscle inflammation and weakness, as well as associated skin changes. “The way people have thought about this disease for a couple of decades is that the muscle injury is an end product of capillary injury,” said Dr. Greenberg at the Congress of Clinical Rheumatology. “It has largely been believed that dermatomyositis is a disease in which antibodies are binding to an endothelial cell antigen, causing complement-mediated injury in capillaries, and that the capillary injury eventually causes ischemia to muscle. According to this model, the characteristic perifascicular atrophy is thought to simply be a result of lack of blood supply to muscle.”

There are a number of problems with this theoretical model, Dr. Greenberg explained. “Importantly, no antigens or antibodies have been demonstrated and, in experimental models of ischemia, perifascicular atrophy doesn't occur. Experimental ischemic myopathy actually affects the central portions of fascicles, not the peripheral portions,” he said. “Nor does one ever see perifascicular atrophy in vasculitis, the one disease in which we do know there is muscular ischemia.”

Plasmacytoid dendritic cells, which produce alpha and beta interferons, have recently been identified in the muscle and skin of patients with dermatomyositis. Gene-expression profiling of these cells shows significant up-regulation of type I interferon-alpha/-beta-inducible genes that correlates with disease activity. These findings suggest a different mechanistic model, said Dr. Greenberg. “One potential way to think about this disease is that the overproduction of type I interferon-usable proteins, regardless of the mechanism, may be separately injuring both capillaries and the perifascicular muscle fibers,” he said.

“There are muscle fibers that appear to be dying for no apparent reason. There are no immunoglobulin molecules; there are no T cells touching them,” said Dr. Greenberg. “The question that arises is whether the production of some interferon-inducible transcript or protein within myofibers themselves could injure the muscle fibers,” he said.

“Is this an autoimmune disease in which tissue injury results from the intracellular proteins of the innate immune system, rather than by-products of the adaptive immune system, either in the immunoglobulin molecules secreted by plasma cells or effector cytotoxic molecules secreted by CD8 plasma T cells?”

Given this possibility, “it is very reasonable to try blocking interferon-alpha or its receptor for the treatment of dermatomyositis,” said Dr. Greenberg. The paradigm for muscle injury in inclusion body myositis (IBM) and polymyositis should also be revisited in light of recent “surprises,” according to Dr. Greenberg. Both diseases have long been considered “classic intramuscular CD8 T-cell-mediated diseases.” However, recent research has demonstrated an abundance of both myeloid dendritic cells (which are implicated in triggering the adaptive immune system) and differentiated B cells (in the form of CD138+ plasma cells) in the inflamed muscle tissue of patients with either IBM or polymyositis.

These findings, taken together, broaden the pool of potential therapeutic agents. “There are at lease 15 [Food and Drug Administration]-approved drugs targeting these molecules of interest,” said Dr. Greenberg.

He disclosed having a sponsored-research agreement with MedImmune for support of his research laboratory, but noted that all data discussed in this presentation were obtained prior to this agreement.

MONTREAL — Evidence of significant brain inflammation and neuronal damage in patients with clinically stable HIV infection suggests that central nervous system injury persists despite successful viral control, Dr. Bradford Navia reported at the Conference on Retroviruses and Opportunistic Illnesses.

He and his colleagues in the multicenter HIV Neuroimaging Consortium used a combined imaging approach to prospectively examine the effects of HIV on brain function and identify biomarkers of risk and progression of cognitive impairment in 240 HIV-positive subjects, which they then compared with findings from 28 HIV-negative control subjects. To be included in the study, HIV patients had to have been on highly active antiretroviral therapy (HAART) for at least 1 year and their nadir CD4 count had to be less than 200 cells/mm

The HIV-positive subjects were classified into three groups: 124 were neurologically asymptomatic, 66 had AIDS dementia complex (ADC) stage 0.5, and 50 had ADC stage 1–3. The median age of the HIV group was 47 years, and the average duration of HIV infection was about 12 years. The median CD4 count was 309 cells/mm

Neurologic, neuropsychological, and medical assessments were performed at baseline and every 6–8 months, along with plasma and CSF viral load measurement and ADC staging. Also, magnetic resonance imaging and magnetic resonance spectroscopy were used to determine a neuronal biomarker—N-acetyl aspartate/creatinine ratio (NAA/Cr)—and two inflammatory markers—the choline/creatinine ratio (Cho/Cr) and the myoinositol/creatinine ratio (MI/Cr)—in the basal ganglia, frontal white matter, and midfrontal cortex.

At baseline, the brains of the HIV-positive patients had increased levels of inflammatory proteins, independent of cognitive status. Compared with subjects in the control group, the HIV-positive patients had increased MI/Cr in all three brain regions and increased Cho/Cr in the midfrontal cortex. Over time, MI/Cr increased significantly in the frontal white matter and the midfrontal cortex, and Cho/Cr increased significantly in the midfrontal cortex.

Among HIV-positive patients who had cognitive impairment, NAA/Cr was decreased in the frontal white matter, compared with the controls and the asymptomatic HIV patients. NAA/Cr decreased significantly over time in the frontal white matter and basal ganglia of these symptomatic patients, Dr. Navia reported.

A predictive model incorporating patient demographics and disease-specific variables identified four metabolic patterns of brain injury and ADC stage. One of these patterns—basal ganglia with decreased NAA/Cr and increased Cho/Cr—emerged as a significant predictor of ADC stage 1–3. This suggests that the brain injury process in HIV infection may have two stages, with preliminary, diffuse inflammation followed by basal ganglia disease as ADC develops, he said.

The findings suggest that diffuse inflammatory changes can occur in the brains of HAART-treated HIV-infected patients in the absence of neurologic symptoms. Also, decreasing NAA/Cr in the basal ganglia is a critical event in patients with ADC “and may provide a sensitive biomarker of the extent of structural and functional change in the brain.”

Dr. Navia reported no relevant financial conflicts of interest.

MONTREAL — Evidence of significant brain inflammation and neuronal damage in patients with clinically stable HIV infection suggests that central nervous system injury persists despite successful viral control, Dr. Bradford Navia reported at the Conference on Retroviruses and Opportunistic Illnesses.

He and his colleagues in the multicenter HIV Neuroimaging Consortium used a combined imaging approach to prospectively examine the effects of HIV on brain function and identify biomarkers of risk and progression of cognitive impairment in 240 HIV-positive subjects, which they then compared with findings from 28 HIV-negative control subjects. To be included in the study, HIV patients had to have been on highly active antiretroviral therapy (HAART) for at least 1 year and their nadir CD4 count had to be less than 200 cells/mm

The HIV-positive subjects were classified into three groups: 124 were neurologically asymptomatic, 66 had AIDS dementia complex (ADC) stage 0.5, and 50 had ADC stage 1–3. The median age of the HIV group was 47 years, and the average duration of HIV infection was about 12 years. The median CD4 count was 309 cells/mm

Neurologic, neuropsychological, and medical assessments were performed at baseline and every 6–8 months, along with plasma and CSF viral load measurement and ADC staging. Also, magnetic resonance imaging and magnetic resonance spectroscopy were used to determine a neuronal biomarker—N-acetyl aspartate/creatinine ratio (NAA/Cr)—and two inflammatory markers—the choline/creatinine ratio (Cho/Cr) and the myoinositol/creatinine ratio (MI/Cr)—in the basal ganglia, frontal white matter, and midfrontal cortex.

At baseline, the brains of the HIV-positive patients had increased levels of inflammatory proteins, independent of cognitive status. Compared with subjects in the control group, the HIV-positive patients had increased MI/Cr in all three brain regions and increased Cho/Cr in the midfrontal cortex. Over time, MI/Cr increased significantly in the frontal white matter and the midfrontal cortex, and Cho/Cr increased significantly in the midfrontal cortex.

Among HIV-positive patients who had cognitive impairment, NAA/Cr was decreased in the frontal white matter, compared with the controls and the asymptomatic HIV patients. NAA/Cr decreased significantly over time in the frontal white matter and basal ganglia of these symptomatic patients, Dr. Navia reported.

A predictive model incorporating patient demographics and disease-specific variables identified four metabolic patterns of brain injury and ADC stage. One of these patterns—basal ganglia with decreased NAA/Cr and increased Cho/Cr—emerged as a significant predictor of ADC stage 1–3. This suggests that the brain injury process in HIV infection may have two stages, with preliminary, diffuse inflammation followed by basal ganglia disease as ADC develops, he said.

The findings suggest that diffuse inflammatory changes can occur in the brains of HAART-treated HIV-infected patients in the absence of neurologic symptoms. Also, decreasing NAA/Cr in the basal ganglia is a critical event in patients with ADC “and may provide a sensitive biomarker of the extent of structural and functional change in the brain.”

Dr. Navia reported no relevant financial conflicts of interest.

MONTREAL — Evidence of significant brain inflammation and neuronal damage in patients with clinically stable HIV infection suggests that central nervous system injury persists despite successful viral control, Dr. Bradford Navia reported at the Conference on Retroviruses and Opportunistic Illnesses.

He and his colleagues in the multicenter HIV Neuroimaging Consortium used a combined imaging approach to prospectively examine the effects of HIV on brain function and identify biomarkers of risk and progression of cognitive impairment in 240 HIV-positive subjects, which they then compared with findings from 28 HIV-negative control subjects. To be included in the study, HIV patients had to have been on highly active antiretroviral therapy (HAART) for at least 1 year and their nadir CD4 count had to be less than 200 cells/mm

The HIV-positive subjects were classified into three groups: 124 were neurologically asymptomatic, 66 had AIDS dementia complex (ADC) stage 0.5, and 50 had ADC stage 1–3. The median age of the HIV group was 47 years, and the average duration of HIV infection was about 12 years. The median CD4 count was 309 cells/mm

Neurologic, neuropsychological, and medical assessments were performed at baseline and every 6–8 months, along with plasma and CSF viral load measurement and ADC staging. Also, magnetic resonance imaging and magnetic resonance spectroscopy were used to determine a neuronal biomarker—N-acetyl aspartate/creatinine ratio (NAA/Cr)—and two inflammatory markers—the choline/creatinine ratio (Cho/Cr) and the myoinositol/creatinine ratio (MI/Cr)—in the basal ganglia, frontal white matter, and midfrontal cortex.

At baseline, the brains of the HIV-positive patients had increased levels of inflammatory proteins, independent of cognitive status. Compared with subjects in the control group, the HIV-positive patients had increased MI/Cr in all three brain regions and increased Cho/Cr in the midfrontal cortex. Over time, MI/Cr increased significantly in the frontal white matter and the midfrontal cortex, and Cho/Cr increased significantly in the midfrontal cortex.

Among HIV-positive patients who had cognitive impairment, NAA/Cr was decreased in the frontal white matter, compared with the controls and the asymptomatic HIV patients. NAA/Cr decreased significantly over time in the frontal white matter and basal ganglia of these symptomatic patients, Dr. Navia reported.

A predictive model incorporating patient demographics and disease-specific variables identified four metabolic patterns of brain injury and ADC stage. One of these patterns—basal ganglia with decreased NAA/Cr and increased Cho/Cr—emerged as a significant predictor of ADC stage 1–3. This suggests that the brain injury process in HIV infection may have two stages, with preliminary, diffuse inflammation followed by basal ganglia disease as ADC develops, he said.

The findings suggest that diffuse inflammatory changes can occur in the brains of HAART-treated HIV-infected patients in the absence of neurologic symptoms. Also, decreasing NAA/Cr in the basal ganglia is a critical event in patients with ADC “and may provide a sensitive biomarker of the extent of structural and functional change in the brain.”

Dr. Navia reported no relevant financial conflicts of interest.

MONTREAL — HIV patients who are coinfected with the hepatitis C virus have significantly higher rates of health care utilization and disability days than do those with HIV alone.

The findings, according to lead investigator Benjamin Linas of Boston's Massachusetts General Hospital, “suggest that hepatitis C coinfection generates substantial additional burdens on the system of care for HIV-infected patients.”

With an estimated prevalence of up to 30%, hepatitis C virus (HCV) coinfection is a growing cause of morbidity and mortality in HIV-infected patients, Dr. Linas said at the Conference on Retroviruses and Opportunistic Infections.

To assess the public health burden of coinfection in this population, he and his colleagues analyzed data from the National Institutes of Health-sponsored AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials cohort. The cohort of 3,087 patients was predominantly male (83%) and had a median age of 39 years. The median CD4 cell count at enrollment was 244 cells/mm

Of the full cohort, 359 (12%) were coinfected with HCV. When coinfected patients were compared with monoinfected patients, “the adjusted rate ratios for nights spent in the hospital, emergency department visits, and disability days were 1.9, 1.7, and 1.4, respectively,” he said.

“HIV/HCV coinfected patients can expect 1.5- to 2-times higher rates of hospitalizations, emergency department visits, and disability days than would be expected from a similar population of HIV monoinfected patients,” he said.

Dr. Linas reported having no relevant financial disclosures.

MONTREAL — HIV patients who are coinfected with the hepatitis C virus have significantly higher rates of health care utilization and disability days than do those with HIV alone.

The findings, according to lead investigator Benjamin Linas of Boston's Massachusetts General Hospital, “suggest that hepatitis C coinfection generates substantial additional burdens on the system of care for HIV-infected patients.”

With an estimated prevalence of up to 30%, hepatitis C virus (HCV) coinfection is a growing cause of morbidity and mortality in HIV-infected patients, Dr. Linas said at the Conference on Retroviruses and Opportunistic Infections.

To assess the public health burden of coinfection in this population, he and his colleagues analyzed data from the National Institutes of Health-sponsored AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials cohort. The cohort of 3,087 patients was predominantly male (83%) and had a median age of 39 years. The median CD4 cell count at enrollment was 244 cells/mm

Of the full cohort, 359 (12%) were coinfected with HCV. When coinfected patients were compared with monoinfected patients, “the adjusted rate ratios for nights spent in the hospital, emergency department visits, and disability days were 1.9, 1.7, and 1.4, respectively,” he said.

“HIV/HCV coinfected patients can expect 1.5- to 2-times higher rates of hospitalizations, emergency department visits, and disability days than would be expected from a similar population of HIV monoinfected patients,” he said.

Dr. Linas reported having no relevant financial disclosures.

MONTREAL — HIV patients who are coinfected with the hepatitis C virus have significantly higher rates of health care utilization and disability days than do those with HIV alone.

The findings, according to lead investigator Benjamin Linas of Boston's Massachusetts General Hospital, “suggest that hepatitis C coinfection generates substantial additional burdens on the system of care for HIV-infected patients.”

With an estimated prevalence of up to 30%, hepatitis C virus (HCV) coinfection is a growing cause of morbidity and mortality in HIV-infected patients, Dr. Linas said at the Conference on Retroviruses and Opportunistic Infections.

To assess the public health burden of coinfection in this population, he and his colleagues analyzed data from the National Institutes of Health-sponsored AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials cohort. The cohort of 3,087 patients was predominantly male (83%) and had a median age of 39 years. The median CD4 cell count at enrollment was 244 cells/mm

Of the full cohort, 359 (12%) were coinfected with HCV. When coinfected patients were compared with monoinfected patients, “the adjusted rate ratios for nights spent in the hospital, emergency department visits, and disability days were 1.9, 1.7, and 1.4, respectively,” he said.

“HIV/HCV coinfected patients can expect 1.5- to 2-times higher rates of hospitalizations, emergency department visits, and disability days than would be expected from a similar population of HIV monoinfected patients,” he said.

Dr. Linas reported having no relevant financial disclosures.

MONTREAL — A drug approved for use in diabetes may reverse HIV-associated lipoatrophy and insulin resistance, a study has shown.

In a randomized, controlled trial of 71 HIV-positive patients with documented peripheral fat wasting, patients who received 4 mg of the thiazolidinedione agent rosiglitazone (Avandia) twice daily for 48 weeks had significant gains in limb fat, and decreases in insulin resistance and insulin levels, compared with patients on placebo, Dr. Grace McComsey reported at the Conference on Retroviruses and Opportunistic Infections.

All patients had been treated for at least 12 months (but not during the 6 months prior to study enrollment) with one of the thymidine nucleoside reverse transcriptase inhibitor (tNRTI) drugs that have been linked to lipoatrophy, said Dr. McComsey of Case Western Reserve University in Cleveland.

Lipoatrophy is cosmetically disturbing and stigmatizing for individuals with HIV, and has been linked to decreased adherence to antiretroviral therapy as well as lipid and glycemic abnormalities associated with an increased risk for myocardial infarction and atherosclerotic disease, Dr. McComsey noted.

In vitro studies have suggested that drugs in the glitazone class stimulate production of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) protein, which plays a key role in adipocyte differentiation, and clinical trials have linked the drugs to increased subcutaneous fat in people with diabetes. But data from HIV studies have been mixed, Dr. McComsey said. Many of the clinical trials in HIV have included patients who have remained on the tNRTI drugs zidovudine or stavudine, which inhibit PPAR-gamma, so “it is possible that the two drugs cancel each other out with respect to the effect on lipoatrophy,” she said. The current study is the first to assess the effect of a glitazone on lipoatrophy in HIV-infected patients on tNRTI-sparing regimens, she added.

More than 90% of the patients in the current study had well-controlled HIV, with a viral load less than 400 copies/mL and a mean CD4 cell count between 600 and 700 cells/mm

At baseline, the mean limb fat measures in the rosiglitazone and placebo groups were statistically similar, at 6,533 g and 6,413 g. Baseline lipid and glycemic characteristics also were similar, except for a higher mean total cholesterol level in the placebo arm, Dr. McComsey reported.

At week 48, both groups had increased limb fat consistent with the absence of tNRTIs, Dr. McComsey said. The mean 911-g increase in the treatment group was significantly greater than the mean 253-g increase in the placebo group, she said, and only the treatment arm had decreases from baseline in the mean homeostasis model assessment for insulin resistance and insulin levels.

Total cholesterol levels were significantly higher in the treatment group after 48 weeks, but triglyceride and non-HDL cholesterol levels did not change significantly within or between groups, Dr. McComsey said. Similarly, total bone mineral density, CD4 cell count, and body mass index did not change.

Because some studies in the general population have linked rosiglitazone with an increased risk of cardiovascular disease and decreases in bone density leading to fracture risk, Dr. McComsey and her colleagues are currently analyzing the drug's effect on markers for atherosclerosis, inflammation, and bone status in patients with HIV, she said.

Dr. McComsey reported no relevant financial conflicts of interest.

The mean 911-g increase in limb fat with treatment was significantly greater than the 253-g increase with placebo. DR. MCCOMSEY

MONTREAL — A drug approved for use in diabetes may reverse HIV-associated lipoatrophy and insulin resistance, a study has shown.

In a randomized, controlled trial of 71 HIV-positive patients with documented peripheral fat wasting, patients who received 4 mg of the thiazolidinedione agent rosiglitazone (Avandia) twice daily for 48 weeks had significant gains in limb fat, and decreases in insulin resistance and insulin levels, compared with patients on placebo, Dr. Grace McComsey reported at the Conference on Retroviruses and Opportunistic Infections.

All patients had been treated for at least 12 months (but not during the 6 months prior to study enrollment) with one of the thymidine nucleoside reverse transcriptase inhibitor (tNRTI) drugs that have been linked to lipoatrophy, said Dr. McComsey of Case Western Reserve University in Cleveland.

Lipoatrophy is cosmetically disturbing and stigmatizing for individuals with HIV, and has been linked to decreased adherence to antiretroviral therapy as well as lipid and glycemic abnormalities associated with an increased risk for myocardial infarction and atherosclerotic disease, Dr. McComsey noted.

In vitro studies have suggested that drugs in the glitazone class stimulate production of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) protein, which plays a key role in adipocyte differentiation, and clinical trials have linked the drugs to increased subcutaneous fat in people with diabetes. But data from HIV studies have been mixed, Dr. McComsey said. Many of the clinical trials in HIV have included patients who have remained on the tNRTI drugs zidovudine or stavudine, which inhibit PPAR-gamma, so “it is possible that the two drugs cancel each other out with respect to the effect on lipoatrophy,” she said. The current study is the first to assess the effect of a glitazone on lipoatrophy in HIV-infected patients on tNRTI-sparing regimens, she added.

More than 90% of the patients in the current study had well-controlled HIV, with a viral load less than 400 copies/mL and a mean CD4 cell count between 600 and 700 cells/mm

At baseline, the mean limb fat measures in the rosiglitazone and placebo groups were statistically similar, at 6,533 g and 6,413 g. Baseline lipid and glycemic characteristics also were similar, except for a higher mean total cholesterol level in the placebo arm, Dr. McComsey reported.

At week 48, both groups had increased limb fat consistent with the absence of tNRTIs, Dr. McComsey said. The mean 911-g increase in the treatment group was significantly greater than the mean 253-g increase in the placebo group, she said, and only the treatment arm had decreases from baseline in the mean homeostasis model assessment for insulin resistance and insulin levels.

Total cholesterol levels were significantly higher in the treatment group after 48 weeks, but triglyceride and non-HDL cholesterol levels did not change significantly within or between groups, Dr. McComsey said. Similarly, total bone mineral density, CD4 cell count, and body mass index did not change.

Because some studies in the general population have linked rosiglitazone with an increased risk of cardiovascular disease and decreases in bone density leading to fracture risk, Dr. McComsey and her colleagues are currently analyzing the drug's effect on markers for atherosclerosis, inflammation, and bone status in patients with HIV, she said.

Dr. McComsey reported no relevant financial conflicts of interest.

The mean 911-g increase in limb fat with treatment was significantly greater than the 253-g increase with placebo. DR. MCCOMSEY

MONTREAL — A drug approved for use in diabetes may reverse HIV-associated lipoatrophy and insulin resistance, a study has shown.

In a randomized, controlled trial of 71 HIV-positive patients with documented peripheral fat wasting, patients who received 4 mg of the thiazolidinedione agent rosiglitazone (Avandia) twice daily for 48 weeks had significant gains in limb fat, and decreases in insulin resistance and insulin levels, compared with patients on placebo, Dr. Grace McComsey reported at the Conference on Retroviruses and Opportunistic Infections.

All patients had been treated for at least 12 months (but not during the 6 months prior to study enrollment) with one of the thymidine nucleoside reverse transcriptase inhibitor (tNRTI) drugs that have been linked to lipoatrophy, said Dr. McComsey of Case Western Reserve University in Cleveland.

Lipoatrophy is cosmetically disturbing and stigmatizing for individuals with HIV, and has been linked to decreased adherence to antiretroviral therapy as well as lipid and glycemic abnormalities associated with an increased risk for myocardial infarction and atherosclerotic disease, Dr. McComsey noted.

In vitro studies have suggested that drugs in the glitazone class stimulate production of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) protein, which plays a key role in adipocyte differentiation, and clinical trials have linked the drugs to increased subcutaneous fat in people with diabetes. But data from HIV studies have been mixed, Dr. McComsey said. Many of the clinical trials in HIV have included patients who have remained on the tNRTI drugs zidovudine or stavudine, which inhibit PPAR-gamma, so “it is possible that the two drugs cancel each other out with respect to the effect on lipoatrophy,” she said. The current study is the first to assess the effect of a glitazone on lipoatrophy in HIV-infected patients on tNRTI-sparing regimens, she added.

More than 90% of the patients in the current study had well-controlled HIV, with a viral load less than 400 copies/mL and a mean CD4 cell count between 600 and 700 cells/mm

At baseline, the mean limb fat measures in the rosiglitazone and placebo groups were statistically similar, at 6,533 g and 6,413 g. Baseline lipid and glycemic characteristics also were similar, except for a higher mean total cholesterol level in the placebo arm, Dr. McComsey reported.

At week 48, both groups had increased limb fat consistent with the absence of tNRTIs, Dr. McComsey said. The mean 911-g increase in the treatment group was significantly greater than the mean 253-g increase in the placebo group, she said, and only the treatment arm had decreases from baseline in the mean homeostasis model assessment for insulin resistance and insulin levels.

Total cholesterol levels were significantly higher in the treatment group after 48 weeks, but triglyceride and non-HDL cholesterol levels did not change significantly within or between groups, Dr. McComsey said. Similarly, total bone mineral density, CD4 cell count, and body mass index did not change.

Because some studies in the general population have linked rosiglitazone with an increased risk of cardiovascular disease and decreases in bone density leading to fracture risk, Dr. McComsey and her colleagues are currently analyzing the drug's effect on markers for atherosclerosis, inflammation, and bone status in patients with HIV, she said.

Dr. McComsey reported no relevant financial conflicts of interest.

The mean 911-g increase in limb fat with treatment was significantly greater than the 253-g increase with placebo. DR. MCCOMSEY

MONTREAL — Evidence of significant brain inflammation and neuronal damage in patients with clinically stable HIV infection suggests that central nervous system injury persists despite successful viral control, Dr. Bradford Navia reported at the Conference on Retroviruses and Opportunistic Illnesses.

He and his colleagues in the multicenter HIV Neuroimaging Consortium used a combined imaging approach to prospectively examine the effects of HIV on brain function and identify biomarkers of risk and progression of cognitive impairment in 240 HIV-positive subjects, which they then compared with findings from 28 HIV-negative control subjects. To be included in the study, HIV patients had to have been on highly active antiretroviral therapy (HAART) for at least 1 year and their nadir CD4 count had to be less than 200 cells/mm

The HIV-positive subjects were classified into three groups: 124 were neurologically asymptomatic, 66 had AIDS dementia complex (ADC) stage 0.5, and 50 had ADC stage 1–3. The median age of the HIV group was 47 years, and the average duration of HIV infection was about 12 years. The median CD4 count was 309 cells/mm

Neurologic, neuropsychological, and medical assessments were performed at baseline and every 6–8 months, along with plasma and CSF viral load measurement and ADC staging. Also, magnetic resonance imaging and magnetic resonance spectroscopy were used to determine a neuronal biomarker—N-acetyl aspartate/creatinine ratio (NAA/Cr)—and two inflammatory markers—the choline/creatinine ratio (Cho/Cr) and the myoinositol/creatinine ratio (MI/Cr)—in the basal ganglia, frontal white matter, and midfrontal cortex.

At baseline, the brains of the HIV-positive patients had increased levels of inflammatory proteins, independent of cognitive status. Compared with subjects in the control group, the HIV-positive patients had increased MI/Cr in all three brain regions and increased Cho/Cr in the midfrontal cortex. Over time, MI/Cr increased significantly in the frontal white matter and the midfrontal cortex, and Cho/CR increased significantly in the midfrontal cortex.

Among HIV-positive patients who had cognitive impairment, NAA/Cr was decreased in the frontal white matter, compared with the controls and the asymptomatic HIV patients. NAA/Cr decreased significantly over time in the frontal white matter and basal ganglia of these symptomatic patients, Dr. Navia reported.

A predictive model incorporating patient demographics and disease-specific variables identified four metabolic patterns of brain injury and ADC stage. Following logistic regression analysis, one of these patterns—basal ganglia with decreased NAA/Cr and increased Cho/Cr—emerged as a significant predictor of ADC stage 1–3. This suggests that the brain injury process in HIV infection may have two stages, with preliminary, diffuse inflammation followed by basal ganglia disease as ADC develops, he said.

The findings suggest that diffuse inflammatory changes can occur in the brains of HAART-treated HIV-infected patients in the absence of neurologic symptoms. Also, decreasing NAA/Cr in the basal ganglia is a critical event in patients with ADC and may provide a biomarker of the extent of changes in the brain, said Dr. Navia who reported no conflicts of interest.

MONTREAL — Evidence of significant brain inflammation and neuronal damage in patients with clinically stable HIV infection suggests that central nervous system injury persists despite successful viral control, Dr. Bradford Navia reported at the Conference on Retroviruses and Opportunistic Illnesses.

He and his colleagues in the multicenter HIV Neuroimaging Consortium used a combined imaging approach to prospectively examine the effects of HIV on brain function and identify biomarkers of risk and progression of cognitive impairment in 240 HIV-positive subjects, which they then compared with findings from 28 HIV-negative control subjects. To be included in the study, HIV patients had to have been on highly active antiretroviral therapy (HAART) for at least 1 year and their nadir CD4 count had to be less than 200 cells/mm

The HIV-positive subjects were classified into three groups: 124 were neurologically asymptomatic, 66 had AIDS dementia complex (ADC) stage 0.5, and 50 had ADC stage 1–3. The median age of the HIV group was 47 years, and the average duration of HIV infection was about 12 years. The median CD4 count was 309 cells/mm

Neurologic, neuropsychological, and medical assessments were performed at baseline and every 6–8 months, along with plasma and CSF viral load measurement and ADC staging. Also, magnetic resonance imaging and magnetic resonance spectroscopy were used to determine a neuronal biomarker—N-acetyl aspartate/creatinine ratio (NAA/Cr)—and two inflammatory markers—the choline/creatinine ratio (Cho/Cr) and the myoinositol/creatinine ratio (MI/Cr)—in the basal ganglia, frontal white matter, and midfrontal cortex.

At baseline, the brains of the HIV-positive patients had increased levels of inflammatory proteins, independent of cognitive status. Compared with subjects in the control group, the HIV-positive patients had increased MI/Cr in all three brain regions and increased Cho/Cr in the midfrontal cortex. Over time, MI/Cr increased significantly in the frontal white matter and the midfrontal cortex, and Cho/CR increased significantly in the midfrontal cortex.

Among HIV-positive patients who had cognitive impairment, NAA/Cr was decreased in the frontal white matter, compared with the controls and the asymptomatic HIV patients. NAA/Cr decreased significantly over time in the frontal white matter and basal ganglia of these symptomatic patients, Dr. Navia reported.

A predictive model incorporating patient demographics and disease-specific variables identified four metabolic patterns of brain injury and ADC stage. Following logistic regression analysis, one of these patterns—basal ganglia with decreased NAA/Cr and increased Cho/Cr—emerged as a significant predictor of ADC stage 1–3. This suggests that the brain injury process in HIV infection may have two stages, with preliminary, diffuse inflammation followed by basal ganglia disease as ADC develops, he said.

The findings suggest that diffuse inflammatory changes can occur in the brains of HAART-treated HIV-infected patients in the absence of neurologic symptoms. Also, decreasing NAA/Cr in the basal ganglia is a critical event in patients with ADC and may provide a biomarker of the extent of changes in the brain, said Dr. Navia who reported no conflicts of interest.

MONTREAL — Evidence of significant brain inflammation and neuronal damage in patients with clinically stable HIV infection suggests that central nervous system injury persists despite successful viral control, Dr. Bradford Navia reported at the Conference on Retroviruses and Opportunistic Illnesses.

He and his colleagues in the multicenter HIV Neuroimaging Consortium used a combined imaging approach to prospectively examine the effects of HIV on brain function and identify biomarkers of risk and progression of cognitive impairment in 240 HIV-positive subjects, which they then compared with findings from 28 HIV-negative control subjects. To be included in the study, HIV patients had to have been on highly active antiretroviral therapy (HAART) for at least 1 year and their nadir CD4 count had to be less than 200 cells/mm

The HIV-positive subjects were classified into three groups: 124 were neurologically asymptomatic, 66 had AIDS dementia complex (ADC) stage 0.5, and 50 had ADC stage 1–3. The median age of the HIV group was 47 years, and the average duration of HIV infection was about 12 years. The median CD4 count was 309 cells/mm

Neurologic, neuropsychological, and medical assessments were performed at baseline and every 6–8 months, along with plasma and CSF viral load measurement and ADC staging. Also, magnetic resonance imaging and magnetic resonance spectroscopy were used to determine a neuronal biomarker—N-acetyl aspartate/creatinine ratio (NAA/Cr)—and two inflammatory markers—the choline/creatinine ratio (Cho/Cr) and the myoinositol/creatinine ratio (MI/Cr)—in the basal ganglia, frontal white matter, and midfrontal cortex.

At baseline, the brains of the HIV-positive patients had increased levels of inflammatory proteins, independent of cognitive status. Compared with subjects in the control group, the HIV-positive patients had increased MI/Cr in all three brain regions and increased Cho/Cr in the midfrontal cortex. Over time, MI/Cr increased significantly in the frontal white matter and the midfrontal cortex, and Cho/CR increased significantly in the midfrontal cortex.

Among HIV-positive patients who had cognitive impairment, NAA/Cr was decreased in the frontal white matter, compared with the controls and the asymptomatic HIV patients. NAA/Cr decreased significantly over time in the frontal white matter and basal ganglia of these symptomatic patients, Dr. Navia reported.

A predictive model incorporating patient demographics and disease-specific variables identified four metabolic patterns of brain injury and ADC stage. Following logistic regression analysis, one of these patterns—basal ganglia with decreased NAA/Cr and increased Cho/Cr—emerged as a significant predictor of ADC stage 1–3. This suggests that the brain injury process in HIV infection may have two stages, with preliminary, diffuse inflammation followed by basal ganglia disease as ADC develops, he said.

The findings suggest that diffuse inflammatory changes can occur in the brains of HAART-treated HIV-infected patients in the absence of neurologic symptoms. Also, decreasing NAA/Cr in the basal ganglia is a critical event in patients with ADC and may provide a biomarker of the extent of changes in the brain, said Dr. Navia who reported no conflicts of interest.

Adding clopidogrel to aspirin therapy significantly reduces the risk of stroke and other major vascular events in patients who have atrial fibrillation and are not candidates for anticoagulation therapy with a vitamin K antagonist, according to Dr. Stuart Connolly of the Population Health Research Institute in Hamilton, Ont.

The rate of major vascular events was 6.8% at a median 3.6 years of follow-up among 3,772 study participants randomized to receive 75 mg per day of the oral antiplatelet agent in addition to aspirin in the multicenter Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A). The rate of major vascular events was 7.6% among the 3,782 patients randomized to placebo and aspirin therapy.

The clopidogrel and aspirin regimen was associated “with an acceptable increase in risk of major hemorrhage,” Dr. Connolly reported in a press conference at the annual meeting of the American College of Cardiology.

The rate of major hemorrhage, defined as requiring a transfusion of at least two units of blood, increased from 1.3% in the placebo and aspirin group to 2.0% in the clopidogrel and aspirin group. However, this risk is less than the risk of major hemorrhage that has been reported with warfarin therapy, he said.

Additionally, there was a nonsignificant trend toward an increased risk in fatal strokes from 0.2% per year to 0.3% per year with clopidogrel plus aspirin therapy.

To weigh the benefits and risks of adding clopidogrel to aspirin therapy in this population, consider 1,000 patients treated for 3 years, Dr. Connolly said. Adding clopidogrel would prevent 28 strokes, 17 of which would be disabling or fatal, and would avert six myocardial infarctions, three of which would be fatal, at a cost of 20 major bleeds.

Dr. Connolly emphasized that oral anticoagulation therapy with vitamin K antagonists such as warfarin is still the most effective way to reduce major vascular events in high-risk patients with atrial fibrillation. However, “40%–50% of the patients who are at high risk for stroke because of atrial fibrillation don't receive anticoagulation therapy because they've been judged to be unsuitable for this treatment. For these patients there is a major unmet medical need, which has now been addressed by the results of the ACTIVE-A trial.”

Dr. Connolly and his colleagues in the ACTIVE-A investigation enrolled 7,554 patients who had atrial fibrillation and at least one risk factor for stroke between June 2003 and May 2006. Study participants were deemed either to be unsuitable for warfarin therapy because of bleeding risk or did not want to begin warfarin therapy. The mean patient age was 71 years.

The primary study outcome was any major vascular event, including stroke, non-CNS systemic embolism, myocardial infarction, or vascular death. The secondary outcomes included the occurrence of any of the primary outcomes, as well as major hemorrhage and total mortality, Dr. Connolly explained.

The primary composite outcome was reduced by 11% in the clopidogrel group relative to aspirin only, “a highly statistically significant result,” Dr. Connolly noted. “What is of particular importance, however, is that this effect was driven almost entirely by a substantial reduction in strokes of all severities.” Strokes were reduced from 3.3% per year to 2.4% per year (N. Eng. J. Med. 2009 March 31 [doi: 10.1056/NEJMoa09013101]).

There was a trend of fewer myocardial infarctions, 0.9% per year in the aspirin only group and 0.7% per year in the clopidogrel plus aspirin group, which did not achieve statistical significance, Dr. Connolly said. However the number of heart attacks in the study was relatively small (90 in the clopidogrel group, 115 in the aspirin plus placebo group), reducing the study's power to detect a significant difference. In studies of several other types of patients, clopidogrel has been shown to reduce heart attacks.

Most of the strokes that occurred in this study were either disabling or severe, “and clopidogrel reduces strokes that were both not so severe and the more severe disabling strokes to an almost equal extent,” Dr. Connolly noted.

Dr. Connolly reported receiving consulting fees, lecture fees, and grant support from Sanofi-Aventis, Bristol-Myers Squibb, and Boehringer Ingelheim, and grant support from Portola Pharmaceuticals.

The rate of major vascular events was 6.8% with clopidogrel and aspirin, vs. 7.6% with placebo and aspirin. DR. CONNOLLY

Adding clopidogrel to aspirin therapy significantly reduces the risk of stroke and other major vascular events in patients who have atrial fibrillation and are not candidates for anticoagulation therapy with a vitamin K antagonist, according to Dr. Stuart Connolly of the Population Health Research Institute in Hamilton, Ont.

The rate of major vascular events was 6.8% at a median 3.6 years of follow-up among 3,772 study participants randomized to receive 75 mg per day of the oral antiplatelet agent in addition to aspirin in the multicenter Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A). The rate of major vascular events was 7.6% among the 3,782 patients randomized to placebo and aspirin therapy.

The clopidogrel and aspirin regimen was associated “with an acceptable increase in risk of major hemorrhage,” Dr. Connolly reported in a press conference at the annual meeting of the American College of Cardiology.

The rate of major hemorrhage, defined as requiring a transfusion of at least two units of blood, increased from 1.3% in the placebo and aspirin group to 2.0% in the clopidogrel and aspirin group. However, this risk is less than the risk of major hemorrhage that has been reported with warfarin therapy, he said.

Additionally, there was a nonsignificant trend toward an increased risk in fatal strokes from 0.2% per year to 0.3% per year with clopidogrel plus aspirin therapy.

To weigh the benefits and risks of adding clopidogrel to aspirin therapy in this population, consider 1,000 patients treated for 3 years, Dr. Connolly said. Adding clopidogrel would prevent 28 strokes, 17 of which would be disabling or fatal, and would avert six myocardial infarctions, three of which would be fatal, at a cost of 20 major bleeds.

Dr. Connolly emphasized that oral anticoagulation therapy with vitamin K antagonists such as warfarin is still the most effective way to reduce major vascular events in high-risk patients with atrial fibrillation. However, “40%–50% of the patients who are at high risk for stroke because of atrial fibrillation don't receive anticoagulation therapy because they've been judged to be unsuitable for this treatment. For these patients there is a major unmet medical need, which has now been addressed by the results of the ACTIVE-A trial.”

Dr. Connolly and his colleagues in the ACTIVE-A investigation enrolled 7,554 patients who had atrial fibrillation and at least one risk factor for stroke between June 2003 and May 2006. Study participants were deemed either to be unsuitable for warfarin therapy because of bleeding risk or did not want to begin warfarin therapy. The mean patient age was 71 years.

The primary study outcome was any major vascular event, including stroke, non-CNS systemic embolism, myocardial infarction, or vascular death. The secondary outcomes included the occurrence of any of the primary outcomes, as well as major hemorrhage and total mortality, Dr. Connolly explained.

The primary composite outcome was reduced by 11% in the clopidogrel group relative to aspirin only, “a highly statistically significant result,” Dr. Connolly noted. “What is of particular importance, however, is that this effect was driven almost entirely by a substantial reduction in strokes of all severities.” Strokes were reduced from 3.3% per year to 2.4% per year (N. Eng. J. Med. 2009 March 31 [doi: 10.1056/NEJMoa09013101]).

There was a trend of fewer myocardial infarctions, 0.9% per year in the aspirin only group and 0.7% per year in the clopidogrel plus aspirin group, which did not achieve statistical significance, Dr. Connolly said. However the number of heart attacks in the study was relatively small (90 in the clopidogrel group, 115 in the aspirin plus placebo group), reducing the study's power to detect a significant difference. In studies of several other types of patients, clopidogrel has been shown to reduce heart attacks.

Most of the strokes that occurred in this study were either disabling or severe, “and clopidogrel reduces strokes that were both not so severe and the more severe disabling strokes to an almost equal extent,” Dr. Connolly noted.

Dr. Connolly reported receiving consulting fees, lecture fees, and grant support from Sanofi-Aventis, Bristol-Myers Squibb, and Boehringer Ingelheim, and grant support from Portola Pharmaceuticals.

The rate of major vascular events was 6.8% with clopidogrel and aspirin, vs. 7.6% with placebo and aspirin. DR. CONNOLLY

Adding clopidogrel to aspirin therapy significantly reduces the risk of stroke and other major vascular events in patients who have atrial fibrillation and are not candidates for anticoagulation therapy with a vitamin K antagonist, according to Dr. Stuart Connolly of the Population Health Research Institute in Hamilton, Ont.

The rate of major vascular events was 6.8% at a median 3.6 years of follow-up among 3,772 study participants randomized to receive 75 mg per day of the oral antiplatelet agent in addition to aspirin in the multicenter Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A). The rate of major vascular events was 7.6% among the 3,782 patients randomized to placebo and aspirin therapy.

The clopidogrel and aspirin regimen was associated “with an acceptable increase in risk of major hemorrhage,” Dr. Connolly reported in a press conference at the annual meeting of the American College of Cardiology.

The rate of major hemorrhage, defined as requiring a transfusion of at least two units of blood, increased from 1.3% in the placebo and aspirin group to 2.0% in the clopidogrel and aspirin group. However, this risk is less than the risk of major hemorrhage that has been reported with warfarin therapy, he said.

Additionally, there was a nonsignificant trend toward an increased risk in fatal strokes from 0.2% per year to 0.3% per year with clopidogrel plus aspirin therapy.

To weigh the benefits and risks of adding clopidogrel to aspirin therapy in this population, consider 1,000 patients treated for 3 years, Dr. Connolly said. Adding clopidogrel would prevent 28 strokes, 17 of which would be disabling or fatal, and would avert six myocardial infarctions, three of which would be fatal, at a cost of 20 major bleeds.

Dr. Connolly emphasized that oral anticoagulation therapy with vitamin K antagonists such as warfarin is still the most effective way to reduce major vascular events in high-risk patients with atrial fibrillation. However, “40%–50% of the patients who are at high risk for stroke because of atrial fibrillation don't receive anticoagulation therapy because they've been judged to be unsuitable for this treatment. For these patients there is a major unmet medical need, which has now been addressed by the results of the ACTIVE-A trial.”

Dr. Connolly and his colleagues in the ACTIVE-A investigation enrolled 7,554 patients who had atrial fibrillation and at least one risk factor for stroke between June 2003 and May 2006. Study participants were deemed either to be unsuitable for warfarin therapy because of bleeding risk or did not want to begin warfarin therapy. The mean patient age was 71 years.

The primary study outcome was any major vascular event, including stroke, non-CNS systemic embolism, myocardial infarction, or vascular death. The secondary outcomes included the occurrence of any of the primary outcomes, as well as major hemorrhage and total mortality, Dr. Connolly explained.

The primary composite outcome was reduced by 11% in the clopidogrel group relative to aspirin only, “a highly statistically significant result,” Dr. Connolly noted. “What is of particular importance, however, is that this effect was driven almost entirely by a substantial reduction in strokes of all severities.” Strokes were reduced from 3.3% per year to 2.4% per year (N. Eng. J. Med. 2009 March 31 [doi: 10.1056/NEJMoa09013101]).

There was a trend of fewer myocardial infarctions, 0.9% per year in the aspirin only group and 0.7% per year in the clopidogrel plus aspirin group, which did not achieve statistical significance, Dr. Connolly said. However the number of heart attacks in the study was relatively small (90 in the clopidogrel group, 115 in the aspirin plus placebo group), reducing the study's power to detect a significant difference. In studies of several other types of patients, clopidogrel has been shown to reduce heart attacks.

Most of the strokes that occurred in this study were either disabling or severe, “and clopidogrel reduces strokes that were both not so severe and the more severe disabling strokes to an almost equal extent,” Dr. Connolly noted.

Dr. Connolly reported receiving consulting fees, lecture fees, and grant support from Sanofi-Aventis, Bristol-Myers Squibb, and Boehringer Ingelheim, and grant support from Portola Pharmaceuticals.

The rate of major vascular events was 6.8% with clopidogrel and aspirin, vs. 7.6% with placebo and aspirin. DR. CONNOLLY

The outcomes of some patients with type 2 diabetes appeared to be poorer when they were enrolled in clinics with open access scheduling, in which patients are seen for appointments within 24 hours.

The finding is surprising because open access scheduling has been hailed as a strategy for increasing practice efficiency and improving access to care. The premise is to eliminate appointment backlogs, and patient no-shows.

In a retrospective, cohort study, researchers at the Indiana University School of Medicine compared the impact of open access and traditional scheduling on the care processes and outcomes of 4,060 adult patients with type 2 diabetes. All study participants came from a large health plan and received care between July 1, 2004, and June 30, 2006, at one of six open access clinics or at one of six traditional access clinics.

In adjusted multivariate analyses comparing open access to traditional scheduling, open access scheduling “significantly affected diabetes-related clinical outcomes in the short term,” Dr. Usha Subramanian and colleagues reported. In particular, the quality of care was worse for African American patients, they noted (J. Gen. Intern. Med. 2009 Mar[24]:327-33).

In the open access group, the odds ratio for hemoglobin A_1c testing among African American patients was 0.47 and the odds ratio for microalbumin testing was 0.37, the authors wrote. Additionally, patients in the open access clinics had significantly higher systolic blood pressure at 1 year as did patients in the conventional scheduling clinics. There were no between-group differences in health care utilization outcomes.

The study was conducted among patients in a single health plan located in one city and most patients were of low socioeconomic status, so “results may not generalize to all other settings or patients groups,” they stressed.

Rigorously designed studies are needed to examine open access scheduling more critically, the authors wrote. Such studies should be conducted in multiple health care settings and should incorporate measures for patient satisfaction, continuity of care, and access to care.

The outcomes of some patients with type 2 diabetes appeared to be poorer when they were enrolled in clinics with open access scheduling, in which patients are seen for appointments within 24 hours.

The finding is surprising because open access scheduling has been hailed as a strategy for increasing practice efficiency and improving access to care. The premise is to eliminate appointment backlogs, and patient no-shows.

In a retrospective, cohort study, researchers at the Indiana University School of Medicine compared the impact of open access and traditional scheduling on the care processes and outcomes of 4,060 adult patients with type 2 diabetes. All study participants came from a large health plan and received care between July 1, 2004, and June 30, 2006, at one of six open access clinics or at one of six traditional access clinics.

In adjusted multivariate analyses comparing open access to traditional scheduling, open access scheduling “significantly affected diabetes-related clinical outcomes in the short term,” Dr. Usha Subramanian and colleagues reported. In particular, the quality of care was worse for African American patients, they noted (J. Gen. Intern. Med. 2009 Mar[24]:327-33).

In the open access group, the odds ratio for hemoglobin A_1c testing among African American patients was 0.47 and the odds ratio for microalbumin testing was 0.37, the authors wrote. Additionally, patients in the open access clinics had significantly higher systolic blood pressure at 1 year as did patients in the conventional scheduling clinics. There were no between-group differences in health care utilization outcomes.

The study was conducted among patients in a single health plan located in one city and most patients were of low socioeconomic status, so “results may not generalize to all other settings or patients groups,” they stressed.

Rigorously designed studies are needed to examine open access scheduling more critically, the authors wrote. Such studies should be conducted in multiple health care settings and should incorporate measures for patient satisfaction, continuity of care, and access to care.

The outcomes of some patients with type 2 diabetes appeared to be poorer when they were enrolled in clinics with open access scheduling, in which patients are seen for appointments within 24 hours.

The finding is surprising because open access scheduling has been hailed as a strategy for increasing practice efficiency and improving access to care. The premise is to eliminate appointment backlogs, and patient no-shows.

In a retrospective, cohort study, researchers at the Indiana University School of Medicine compared the impact of open access and traditional scheduling on the care processes and outcomes of 4,060 adult patients with type 2 diabetes. All study participants came from a large health plan and received care between July 1, 2004, and June 30, 2006, at one of six open access clinics or at one of six traditional access clinics.

In adjusted multivariate analyses comparing open access to traditional scheduling, open access scheduling “significantly affected diabetes-related clinical outcomes in the short term,” Dr. Usha Subramanian and colleagues reported. In particular, the quality of care was worse for African American patients, they noted (J. Gen. Intern. Med. 2009 Mar[24]:327-33).

In the open access group, the odds ratio for hemoglobin A_1c testing among African American patients was 0.47 and the odds ratio for microalbumin testing was 0.37, the authors wrote. Additionally, patients in the open access clinics had significantly higher systolic blood pressure at 1 year as did patients in the conventional scheduling clinics. There were no between-group differences in health care utilization outcomes.

The study was conducted among patients in a single health plan located in one city and most patients were of low socioeconomic status, so “results may not generalize to all other settings or patients groups,” they stressed.

Rigorously designed studies are needed to examine open access scheduling more critically, the authors wrote. Such studies should be conducted in multiple health care settings and should incorporate measures for patient satisfaction, continuity of care, and access to care.

The Food and Drug Administration's recent approval of Eli Lilly's olanzapine/fluoxetine combination drug Symbyax for recalcitrant depression has been hailed as an important advance in the management of patients with major depressive disorder, but some experts still advise proceeding with caution.

Already approved for the treatment of bipolar depression, Symbyax is the first agent to be approved for acute therapy of treatment-resistant depression.

Approval of the combination antipsychotic/antidepressant was based on data from five trials demonstrating significant reductions in mean total Montgomery-Åsberg Depression Rating Scale (MADRS) scores relative to either fluoxetine alone or olanzapine alone among patients who met DSM-IV criteria for major depressive disorder (MDD) and who previously did not respond to two antidepressants of adequate dose and duration.

The studies evaluated fixed-combination doses ranging from 6 mg to 18 mg for olanzapine and 25 mg to 50 mg for fluoxetine, according to a press release from Eli Lilly & Co.

In an integrated analysis provided to the FDA by Eli Lilly, the reduction from baseline in mean MADRS scores for the combination drug vs. fluoxetine alone and olanzapine alone was −12.2 vs. −8.5 and −7.7, respectively. The remission rates for the combination, fluoxetine only, and olanzapine only were 25.5%, 17.3%, and 14.0%, respectively.

Pooled data from safety studies showed that, among the adverse events reported in at least 5% of the patients taking the combination drug, weight gain, increased appetite, dry mouth, somnolence, and fatigue were reported at twice the rate of patients in the placebo group.

Considering the large number of patients with treatment-resistant MDD—up to 35% of patients with depression, according to the data provided by Eli Lilly—the approval of the combination therapy is an important development, said Dr. Noah S. Philip of Brown University, Providence, R.I., who has studied the off-label use of atypical antipsychotic drugs in the treatment of depression.

“As the [Sequenced Treatment Alternatives to Relieve Depression] trial demonstrated, approximately one-half of patients respond and one-third remit during their first antidepressant trial, so more options are clearly needed, and use of the atypical antipsychotics as augmenting agents for depression is an increasing pattern to fill this important need.”

However, he noted, “there are still no trials comparing these newer, and much more expensive, augmentation strategies to other … strategies such as lithium, T3, or bupropion augmentation.”

There have also been concerns that definition of treatment-resistant depression in the olanzapine/fluoxetine combination studies might be too lax. “Operationally, the definition of treatment-resistant depression is the failure of at least two previous trials in the current depressive episode [as in the data presented by Lilly to the FDA],” Dr. Philip said. “Other definitions include failure from at least two separate classes of antidepressants within a current major depressive episode, verified by scales such as the Antidepressant Treatment History Form, as well as failed trials of psychotherapy.”

In addition, Dr. Philip said, the data about weight gain with the combination therapy “merit an important discussion. Lilly's data showed that 56% of patients who received olanzapine/fluoxetine combination in longer term treatment (up to 76 weeks) had a more than 7% increase in weight from their baseline, and that patients with early weight gain [first 6 weeks] were more likely to gain even more weight,” he said (J. Clin. Psychiatry 2005;66:1468-76).

The data about weight gain with the combination therapy 'merit an important discussion.' DR. PHILIP

The Food and Drug Administration's recent approval of Eli Lilly's olanzapine/fluoxetine combination drug Symbyax for recalcitrant depression has been hailed as an important advance in the management of patients with major depressive disorder, but some experts still advise proceeding with caution.

Already approved for the treatment of bipolar depression, Symbyax is the first agent to be approved for acute therapy of treatment-resistant depression.

Approval of the combination antipsychotic/antidepressant was based on data from five trials demonstrating significant reductions in mean total Montgomery-Åsberg Depression Rating Scale (MADRS) scores relative to either fluoxetine alone or olanzapine alone among patients who met DSM-IV criteria for major depressive disorder (MDD) and who previously did not respond to two antidepressants of adequate dose and duration.

The studies evaluated fixed-combination doses ranging from 6 mg to 18 mg for olanzapine and 25 mg to 50 mg for fluoxetine, according to a press release from Eli Lilly & Co.

In an integrated analysis provided to the FDA by Eli Lilly, the reduction from baseline in mean MADRS scores for the combination drug vs. fluoxetine alone and olanzapine alone was −12.2 vs. −8.5 and −7.7, respectively. The remission rates for the combination, fluoxetine only, and olanzapine only were 25.5%, 17.3%, and 14.0%, respectively.

Pooled data from safety studies showed that, among the adverse events reported in at least 5% of the patients taking the combination drug, weight gain, increased appetite, dry mouth, somnolence, and fatigue were reported at twice the rate of patients in the placebo group.

Considering the large number of patients with treatment-resistant MDD—up to 35% of patients with depression, according to the data provided by Eli Lilly—the approval of the combination therapy is an important development, said Dr. Noah S. Philip of Brown University, Providence, R.I., who has studied the off-label use of atypical antipsychotic drugs in the treatment of depression.

“As the [Sequenced Treatment Alternatives to Relieve Depression] trial demonstrated, approximately one-half of patients respond and one-third remit during their first antidepressant trial, so more options are clearly needed, and use of the atypical antipsychotics as augmenting agents for depression is an increasing pattern to fill this important need.”

However, he noted, “there are still no trials comparing these newer, and much more expensive, augmentation strategies to other … strategies such as lithium, T3, or bupropion augmentation.”

There have also been concerns that definition of treatment-resistant depression in the olanzapine/fluoxetine combination studies might be too lax. “Operationally, the definition of treatment-resistant depression is the failure of at least two previous trials in the current depressive episode [as in the data presented by Lilly to the FDA],” Dr. Philip said. “Other definitions include failure from at least two separate classes of antidepressants within a current major depressive episode, verified by scales such as the Antidepressant Treatment History Form, as well as failed trials of psychotherapy.”

In addition, Dr. Philip said, the data about weight gain with the combination therapy “merit an important discussion. Lilly's data showed that 56% of patients who received olanzapine/fluoxetine combination in longer term treatment (up to 76 weeks) had a more than 7% increase in weight from their baseline, and that patients with early weight gain [first 6 weeks] were more likely to gain even more weight,” he said (J. Clin. Psychiatry 2005;66:1468-76).

The data about weight gain with the combination therapy 'merit an important discussion.' DR. PHILIP

The Food and Drug Administration's recent approval of Eli Lilly's olanzapine/fluoxetine combination drug Symbyax for recalcitrant depression has been hailed as an important advance in the management of patients with major depressive disorder, but some experts still advise proceeding with caution.

Already approved for the treatment of bipolar depression, Symbyax is the first agent to be approved for acute therapy of treatment-resistant depression.

Approval of the combination antipsychotic/antidepressant was based on data from five trials demonstrating significant reductions in mean total Montgomery-Åsberg Depression Rating Scale (MADRS) scores relative to either fluoxetine alone or olanzapine alone among patients who met DSM-IV criteria for major depressive disorder (MDD) and who previously did not respond to two antidepressants of adequate dose and duration.

The studies evaluated fixed-combination doses ranging from 6 mg to 18 mg for olanzapine and 25 mg to 50 mg for fluoxetine, according to a press release from Eli Lilly & Co.

In an integrated analysis provided to the FDA by Eli Lilly, the reduction from baseline in mean MADRS scores for the combination drug vs. fluoxetine alone and olanzapine alone was −12.2 vs. −8.5 and −7.7, respectively. The remission rates for the combination, fluoxetine only, and olanzapine only were 25.5%, 17.3%, and 14.0%, respectively.

Pooled data from safety studies showed that, among the adverse events reported in at least 5% of the patients taking the combination drug, weight gain, increased appetite, dry mouth, somnolence, and fatigue were reported at twice the rate of patients in the placebo group.

Considering the large number of patients with treatment-resistant MDD—up to 35% of patients with depression, according to the data provided by Eli Lilly—the approval of the combination therapy is an important development, said Dr. Noah S. Philip of Brown University, Providence, R.I., who has studied the off-label use of atypical antipsychotic drugs in the treatment of depression.

“As the [Sequenced Treatment Alternatives to Relieve Depression] trial demonstrated, approximately one-half of patients respond and one-third remit during their first antidepressant trial, so more options are clearly needed, and use of the atypical antipsychotics as augmenting agents for depression is an increasing pattern to fill this important need.”

However, he noted, “there are still no trials comparing these newer, and much more expensive, augmentation strategies to other … strategies such as lithium, T3, or bupropion augmentation.”

There have also been concerns that definition of treatment-resistant depression in the olanzapine/fluoxetine combination studies might be too lax. “Operationally, the definition of treatment-resistant depression is the failure of at least two previous trials in the current depressive episode [as in the data presented by Lilly to the FDA],” Dr. Philip said. “Other definitions include failure from at least two separate classes of antidepressants within a current major depressive episode, verified by scales such as the Antidepressant Treatment History Form, as well as failed trials of psychotherapy.”

In addition, Dr. Philip said, the data about weight gain with the combination therapy “merit an important discussion. Lilly's data showed that 56% of patients who received olanzapine/fluoxetine combination in longer term treatment (up to 76 weeks) had a more than 7% increase in weight from their baseline, and that patients with early weight gain [first 6 weeks] were more likely to gain even more weight,” he said (J. Clin. Psychiatry 2005;66:1468-76).

The data about weight gain with the combination therapy 'merit an important discussion.' DR. PHILIP

Adding clopidogrel to aspirin therapy significantly reduces the risk of stroke and other major vascular events in patients who have atrial fibrillation and are not candidates for anticoagulation therapy with a vitamin K antagonist, according to Dr. Stuart Connolly of the Population Health Research Institute in Hamilton, Ont.

The rate of major vascular events was 6.8% at a median 3.6 years of follow-up among 3,772 study participants randomized to receive 75 mg per day of the oral antiplatelet agent in addition to aspirin in the multicenter Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A). The rate of major vascular events was 7.6% among the 3,782 patients randomized to placebo and aspirin therapy.

The clopidogrel and aspirin regimen was associated “with an acceptable increase in risk of major hemorrhage,” Dr. Connolly reported in a press conference at the annual meeting of the American College of Cardiology.

The rate of major hemorrhage, defined as requiring a transfusion of at least two units of blood, increased from 1.3% in the placebo and aspirin group to 2.0% in the clopidogrel and aspirin group. However, this risk is less than the risk of major hemorrhage that has been reported with warfarin therapy, he said.

Additionally, there was a nonsignificant trend toward an increased risk in fatal strokes from 0.2% per year to 0.3% per year with clopidogrel plus aspirin therapy.

Dr. Connolly emphasized that oral anticoagulation therapy with vitamin K antagonists such as warfarin is still the most effective way to reduce major vascular events in high risk patients with atrial fibrillation. However, “40%-50% of the patients who are at high risk for stroke because of atrial fibrillation don't receive anticoagulation therapy because they've been judged to be unsuitable for this treatment.”

Dr. Connolly and his colleagues enrolled 7,554 patients who had atrial fibrillation and at least one risk factor for stroke between June 2003 and May 2006. Participants were deemed either to be unsuitable for warfarin therapy because of bleeding risk or did not want to begin warfarin. The mean patient age was 71 years.

The primary study outcome was any major vascular event, including stroke, non-central nervous system systemic embolism, myocardial infarction, or vascular death.

The primary composite outcome was reduced by 11% in the clopidogrel group relative to aspirin only, “a highly statistically significant result,” Dr. Connolly noted. “What is of particular importance, however, is that this effect was driven almost entirely by a substantial reduction in strokes of all severities.” Strokes were reduced from 3.3% per year to 2.4% per year.

There was a trend of fewer myocardial infarctions, 0.9% per year in the aspirin only group and 0.7% per year in the clopidogrel plus aspirin group, which didn't achieve statistical significance, Dr. Connolly said. However the number of heart attacks in the study was relatively small [90 in the clopidogrel group; 115 in the aspirin plus placebo group], reducing the study's power to detect a significant difference. In studies of several other types of patients, clopidogrel has been shown to reduce heart attacks.

Dr. Connolly reported receiving consulting fees, lecture fees, and grant support from Sanofi-Aventis, Bristol-Myers Squibb, and Boehringer Ingelheim, and grant support from Portola Pharmaceuticals.

This study was published online in the New England Journal of Medicine (doi 10.1056/NEJMoa09013101

Aspirin plus clopidogrel was associated 'with an acceptable increase in risk of major hemorrhage.' DR. CONNOLLY

Adding clopidogrel to aspirin therapy significantly reduces the risk of stroke and other major vascular events in patients who have atrial fibrillation and are not candidates for anticoagulation therapy with a vitamin K antagonist, according to Dr. Stuart Connolly of the Population Health Research Institute in Hamilton, Ont.

The rate of major vascular events was 6.8% at a median 3.6 years of follow-up among 3,772 study participants randomized to receive 75 mg per day of the oral antiplatelet agent in addition to aspirin in the multicenter Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A). The rate of major vascular events was 7.6% among the 3,782 patients randomized to placebo and aspirin therapy.

The clopidogrel and aspirin regimen was associated “with an acceptable increase in risk of major hemorrhage,” Dr. Connolly reported in a press conference at the annual meeting of the American College of Cardiology.

The rate of major hemorrhage, defined as requiring a transfusion of at least two units of blood, increased from 1.3% in the placebo and aspirin group to 2.0% in the clopidogrel and aspirin group. However, this risk is less than the risk of major hemorrhage that has been reported with warfarin therapy, he said.

Additionally, there was a nonsignificant trend toward an increased risk in fatal strokes from 0.2% per year to 0.3% per year with clopidogrel plus aspirin therapy.

Dr. Connolly emphasized that oral anticoagulation therapy with vitamin K antagonists such as warfarin is still the most effective way to reduce major vascular events in high risk patients with atrial fibrillation. However, “40%-50% of the patients who are at high risk for stroke because of atrial fibrillation don't receive anticoagulation therapy because they've been judged to be unsuitable for this treatment.”

Dr. Connolly and his colleagues enrolled 7,554 patients who had atrial fibrillation and at least one risk factor for stroke between June 2003 and May 2006. Participants were deemed either to be unsuitable for warfarin therapy because of bleeding risk or did not want to begin warfarin. The mean patient age was 71 years.

The primary study outcome was any major vascular event, including stroke, non-central nervous system systemic embolism, myocardial infarction, or vascular death.

The primary composite outcome was reduced by 11% in the clopidogrel group relative to aspirin only, “a highly statistically significant result,” Dr. Connolly noted. “What is of particular importance, however, is that this effect was driven almost entirely by a substantial reduction in strokes of all severities.” Strokes were reduced from 3.3% per year to 2.4% per year.

There was a trend of fewer myocardial infarctions, 0.9% per year in the aspirin only group and 0.7% per year in the clopidogrel plus aspirin group, which didn't achieve statistical significance, Dr. Connolly said. However the number of heart attacks in the study was relatively small [90 in the clopidogrel group; 115 in the aspirin plus placebo group], reducing the study's power to detect a significant difference. In studies of several other types of patients, clopidogrel has been shown to reduce heart attacks.

Dr. Connolly reported receiving consulting fees, lecture fees, and grant support from Sanofi-Aventis, Bristol-Myers Squibb, and Boehringer Ingelheim, and grant support from Portola Pharmaceuticals.

This study was published online in the New England Journal of Medicine (doi 10.1056/NEJMoa09013101

Aspirin plus clopidogrel was associated 'with an acceptable increase in risk of major hemorrhage.' DR. CONNOLLY

Adding clopidogrel to aspirin therapy significantly reduces the risk of stroke and other major vascular events in patients who have atrial fibrillation and are not candidates for anticoagulation therapy with a vitamin K antagonist, according to Dr. Stuart Connolly of the Population Health Research Institute in Hamilton, Ont.

The rate of major vascular events was 6.8% at a median 3.6 years of follow-up among 3,772 study participants randomized to receive 75 mg per day of the oral antiplatelet agent in addition to aspirin in the multicenter Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A). The rate of major vascular events was 7.6% among the 3,782 patients randomized to placebo and aspirin therapy.

The clopidogrel and aspirin regimen was associated “with an acceptable increase in risk of major hemorrhage,” Dr. Connolly reported in a press conference at the annual meeting of the American College of Cardiology.

The rate of major hemorrhage, defined as requiring a transfusion of at least two units of blood, increased from 1.3% in the placebo and aspirin group to 2.0% in the clopidogrel and aspirin group. However, this risk is less than the risk of major hemorrhage that has been reported with warfarin therapy, he said.

Additionally, there was a nonsignificant trend toward an increased risk in fatal strokes from 0.2% per year to 0.3% per year with clopidogrel plus aspirin therapy.

Dr. Connolly emphasized that oral anticoagulation therapy with vitamin K antagonists such as warfarin is still the most effective way to reduce major vascular events in high risk patients with atrial fibrillation. However, “40%-50% of the patients who are at high risk for stroke because of atrial fibrillation don't receive anticoagulation therapy because they've been judged to be unsuitable for this treatment.”

Dr. Connolly and his colleagues enrolled 7,554 patients who had atrial fibrillation and at least one risk factor for stroke between June 2003 and May 2006. Participants were deemed either to be unsuitable for warfarin therapy because of bleeding risk or did not want to begin warfarin. The mean patient age was 71 years.

The primary study outcome was any major vascular event, including stroke, non-central nervous system systemic embolism, myocardial infarction, or vascular death.

The primary composite outcome was reduced by 11% in the clopidogrel group relative to aspirin only, “a highly statistically significant result,” Dr. Connolly noted. “What is of particular importance, however, is that this effect was driven almost entirely by a substantial reduction in strokes of all severities.” Strokes were reduced from 3.3% per year to 2.4% per year.

There was a trend of fewer myocardial infarctions, 0.9% per year in the aspirin only group and 0.7% per year in the clopidogrel plus aspirin group, which didn't achieve statistical significance, Dr. Connolly said. However the number of heart attacks in the study was relatively small [90 in the clopidogrel group; 115 in the aspirin plus placebo group], reducing the study's power to detect a significant difference. In studies of several other types of patients, clopidogrel has been shown to reduce heart attacks.

Dr. Connolly reported receiving consulting fees, lecture fees, and grant support from Sanofi-Aventis, Bristol-Myers Squibb, and Boehringer Ingelheim, and grant support from Portola Pharmaceuticals.

This study was published online in the New England Journal of Medicine (doi 10.1056/NEJMoa09013101

Aspirin plus clopidogrel was associated 'with an acceptable increase in risk of major hemorrhage.' DR. CONNOLLY