Progression of HIV-Associated Dementia Treated With HAART
Progression of HIV-Associated Dementia Treated With HAART
A consecutive series of 96 patients with HIV-associated dementia treated with HAART were studied to identify specific clinical factors associated with an improved response to therapy. The Memorial Sloan-Kettering dementia severity scale and the HIV Dementia Scale were used to assess outcomes. Of 30 patients meeting the inclusion criteria with adequate follow-up, 60% improved neurologically and 40% progressed. There was a trend toward improvement associated with plasma viral suppression, whereas progression was strongly associated with injection drug use history (odds ratio, 13.3). Age, ethnicity, gender, adherence, and predicted CNS penetrance of HAART were not associated with improved outcomes.
The advent of HAART has been accompanied by declines in incidence rates of opportunistic infections, including cytomegalovirus and atypical mycobacterial infections and toxoplasmosis. Yet, this treatment is expensive, placing it out of reach for at least 90% of the world's HIV-infected population. Neurologic complications of HIV infection, including dementia, myelopathy, and sensory neuropathy, tend to occur in persons with advanced disease. They are a significant cause of mortality and morbidity for people who have AIDS. Decreases in incidence rates of HIV-associated dementia (HAD) following the introduction of HAART have been observed by cohort studies and CDC surveillance. However, cognitive impairment eventually develops in 30% of people with AIDS, and frank dementia in about 15%, with an annual incidence after the onset of AIDS of approximately 5%.
The clinical manifestations of HAD predominantly suggest subcortical involvement. Memory deficits, both verbal and nonverbal, and psychomotor slowing are characteristic of HAD. Gait difficulties and depressive symptoms are also common features, while attention, calculations, and language are usually not affected in HAD, at least not initially. The results of neurologic examination are often normal, although there may be impairments of rapid eye and limb movements and diffuse hyperreflexia. Radiologic features of HAD include both central and cortical atrophy and white matter abnormalities that correlate with HIV leukoencephalitis.
The pathogenesis of HAD remains unclear but is thought to originate with entry of HIV into the CNS, either by direct infection of capillary endothelial cells or more likely by ingress of infected monocytes/macrophages. Once HIV establishes infection in the CNS, resident macrophages and microglia become activated and release cytokines, metalloproteinases, and chemokines that contribute to neuronal dysfunction and death. Chemokines can also attract further ingress of monocytes/macrophages, and the local release of metalloproteinases can facilitate breakdown of the blood-brain barrier. In addition, viral proteins including Tat and gp120 as well as tumor necrosis factor a produced by activated monocytes/macrophages may be directly toxic to neurons.
Before the introduction of HAART, patients with HAD typically experienced a rapid deterioration over a few months, with a mean survival of 3 to 6 months. However, in a recent case series before HAART, Bouwman and colleagues found that neurologic progression and survival with HAD was highly variable. About one third of patients with HAD remained cognitively stable and had prolonged survival for more than 12 months. A history of injection drug use (IDU) and presentation with more prominent psychomotor slowing was associated with more rapid neurologic progression.
An open-label trial of zidovudine by Tozzi and colleagues demonstrated clinical improvements in two thirds of patients. Subsequent trials of zidovudine monotherapy have suggested improvements in neuropsychological function and have also shown a dose effect, with more improvement with very high dosages of zidovudine (2000 mg daily). Data from the Multicenter AIDS Cohort Study suggest that combination therapy with or without protease inhibitors is better than monotherapy alone or no treatment at improving HIV-associated cognitive impairment.
Another important study was a placebo-controlled, double-blind study of the reverse transcriptase inhibitor abacavir. Ninety-nine HAD patients receiving stable antiretroviral therapy were randomized to receive either abacavir, 600 mg twice daily, or placebo. During the 12 months of the study, few subjects showed neurologic deterioration (2 in the placebo group, none in the abacavir group). No benefit was demonstrated by adding abacavir to stable antiretroviral therapy, despite good CNS penetration. This study highlights 2 important aspects of HIV dementia in the HAART era: combination therapy may produce improvement that continues over several months, and single-drug additions to antiretroviral regimens generally do not significantly affect clinical outcomes.
The clinical factors that determine individual responses to therapy remain unknown. Several factors may impact the effectiveness of different HAART regimens for treating HIV dementia. The degree of CNS penetrance may be an important variable as underscored by the phenomenon of "CNS escape" -- viral sequestration with high levels of CNS HIV RNA (usually measured in cerebrospinal fluid [CSF]) despite plasma viral suppression. Patients who have received HAART for prolonged periods with poor compliance are probably more susceptible, because medical adherence is a critical factor in maintaining viral suppression. Compliance can be especially challenging for patients with cognitive impairment.
We have designed the following study to examine the natural history of HAD in a series of patients receiving HAART and to identify specific clinical factors that may be associated with an improved response to therapy. Demographic characteristics, HIV risk factors, AIDS-defining illness, plasma viral suppression, adherence rate, and CNS penetrance of therapy were all variables hypothesized to influence the clinical course of HIV dementia in the modern era of HAART.
A consecutive series of 96 patients with HIV-associated dementia treated with HAART were studied to identify specific clinical factors associated with an improved response to therapy. The Memorial Sloan-Kettering dementia severity scale and the HIV Dementia Scale were used to assess outcomes. Of 30 patients meeting the inclusion criteria with adequate follow-up, 60% improved neurologically and 40% progressed. There was a trend toward improvement associated with plasma viral suppression, whereas progression was strongly associated with injection drug use history (odds ratio, 13.3). Age, ethnicity, gender, adherence, and predicted CNS penetrance of HAART were not associated with improved outcomes.
The advent of HAART has been accompanied by declines in incidence rates of opportunistic infections, including cytomegalovirus and atypical mycobacterial infections and toxoplasmosis. Yet, this treatment is expensive, placing it out of reach for at least 90% of the world's HIV-infected population. Neurologic complications of HIV infection, including dementia, myelopathy, and sensory neuropathy, tend to occur in persons with advanced disease. They are a significant cause of mortality and morbidity for people who have AIDS. Decreases in incidence rates of HIV-associated dementia (HAD) following the introduction of HAART have been observed by cohort studies and CDC surveillance. However, cognitive impairment eventually develops in 30% of people with AIDS, and frank dementia in about 15%, with an annual incidence after the onset of AIDS of approximately 5%.
The clinical manifestations of HAD predominantly suggest subcortical involvement. Memory deficits, both verbal and nonverbal, and psychomotor slowing are characteristic of HAD. Gait difficulties and depressive symptoms are also common features, while attention, calculations, and language are usually not affected in HAD, at least not initially. The results of neurologic examination are often normal, although there may be impairments of rapid eye and limb movements and diffuse hyperreflexia. Radiologic features of HAD include both central and cortical atrophy and white matter abnormalities that correlate with HIV leukoencephalitis.
The pathogenesis of HAD remains unclear but is thought to originate with entry of HIV into the CNS, either by direct infection of capillary endothelial cells or more likely by ingress of infected monocytes/macrophages. Once HIV establishes infection in the CNS, resident macrophages and microglia become activated and release cytokines, metalloproteinases, and chemokines that contribute to neuronal dysfunction and death. Chemokines can also attract further ingress of monocytes/macrophages, and the local release of metalloproteinases can facilitate breakdown of the blood-brain barrier. In addition, viral proteins including Tat and gp120 as well as tumor necrosis factor a produced by activated monocytes/macrophages may be directly toxic to neurons.
Before the introduction of HAART, patients with HAD typically experienced a rapid deterioration over a few months, with a mean survival of 3 to 6 months. However, in a recent case series before HAART, Bouwman and colleagues found that neurologic progression and survival with HAD was highly variable. About one third of patients with HAD remained cognitively stable and had prolonged survival for more than 12 months. A history of injection drug use (IDU) and presentation with more prominent psychomotor slowing was associated with more rapid neurologic progression.
An open-label trial of zidovudine by Tozzi and colleagues demonstrated clinical improvements in two thirds of patients. Subsequent trials of zidovudine monotherapy have suggested improvements in neuropsychological function and have also shown a dose effect, with more improvement with very high dosages of zidovudine (2000 mg daily). Data from the Multicenter AIDS Cohort Study suggest that combination therapy with or without protease inhibitors is better than monotherapy alone or no treatment at improving HIV-associated cognitive impairment.
Another important study was a placebo-controlled, double-blind study of the reverse transcriptase inhibitor abacavir. Ninety-nine HAD patients receiving stable antiretroviral therapy were randomized to receive either abacavir, 600 mg twice daily, or placebo. During the 12 months of the study, few subjects showed neurologic deterioration (2 in the placebo group, none in the abacavir group). No benefit was demonstrated by adding abacavir to stable antiretroviral therapy, despite good CNS penetration. This study highlights 2 important aspects of HIV dementia in the HAART era: combination therapy may produce improvement that continues over several months, and single-drug additions to antiretroviral regimens generally do not significantly affect clinical outcomes.
The clinical factors that determine individual responses to therapy remain unknown. Several factors may impact the effectiveness of different HAART regimens for treating HIV dementia. The degree of CNS penetrance may be an important variable as underscored by the phenomenon of "CNS escape" -- viral sequestration with high levels of CNS HIV RNA (usually measured in cerebrospinal fluid [CSF]) despite plasma viral suppression. Patients who have received HAART for prolonged periods with poor compliance are probably more susceptible, because medical adherence is a critical factor in maintaining viral suppression. Compliance can be especially challenging for patients with cognitive impairment.
We have designed the following study to examine the natural history of HAD in a series of patients receiving HAART and to identify specific clinical factors that may be associated with an improved response to therapy. Demographic characteristics, HIV risk factors, AIDS-defining illness, plasma viral suppression, adherence rate, and CNS penetrance of therapy were all variables hypothesized to influence the clinical course of HIV dementia in the modern era of HAART.