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Neurologic Complications of HIV Disease and Their Treatment
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Scott L. Letendre, M.D.1, Ronald J. Ellis, M.D., Ph.D.1, Ian Everall, M.B.B.S., Ph.D.1, Beau Ances, M.D. 2, Ajay Bharti, M.D.1, J. Allen McCutchan, M.D., M.Sc.1
1University of California, San Diego, San Diego, CA,
2Washington University, St. Louis, MO
"Impact of HIV on the brain: Sigma cohort focused on people older than 60 (abstract 459). Brief neuropsychological testing identified that more than half (19 of 37, 51%) were impaired.... As this group reaches their 40s and 50s, their risk for cognitive impairment may be substantially higher than people who do not have HIV. Candidate mechanisms that might affect the aging brain of PLWH include accelerated neurodegeneration of the type that can occur with normal aging, disorders of amyloid (similar to Alzheimer's Disease), or vascular injury that can occur with metabolic disorders such as insulin resistance and dyslipidemia.....
....... Magnetic resonance imaging (MRI) in the CHARTER study, for example, identified that cognitive impairment was associated with loss of brain tissue (atrophy of gray matter, the tissue that contains the cell bodies of neurons) and abnormalities of the remaining tissue (abnormal white matter, the tissue that contains the axons that conduct neuronal impulses)....... identifying evidence of inflammation in people with HIV and evidence of loss of neurons in people with HAND or with fatigue...., people with HIV had worse blood flow to the brain that was similar to people who did not have HIV who were 15 to 20 years older. .....HAND, particularly the more severe HIV-associated dementia, was associated with another finding (type II Alzheimer gliosis), indicating a possible shift in the ways that HIV and ART injure the brain. Overall, these findings indicate that the prevalence of HBP (HIV brain pathology) has remained stable or decreased since the widespread use of combination ART but, despite this, other forms of brain disease are common...... a substantial proportion of effectively treated individuals (<50 in blood) have persistent HIV in the nervous system and that this is associated with worse ART penetration and cognitive impairment.....ART can fail primarily in the CNS and identify a clinical approach that improves the effectiveness of treatment when this occurs. ..... development (maraviroc, vicriviroc) and physicochemical data indicate that both may penetrate into the CNS in therapeutic concentrations"
Overview
Substantial work on the peripheral and central nervous system complications of HIV was presented at the 16th Conference on Retroviruses and Opportunistic Infections. Six studies of more than 4,500 volunteers identified that distal sensory peripheral neuropathy continues to be common, with diagnostic rates ranging from 19% to 66% and varying based on country, disease stage, type of antiretroviral treatment, age, height, and mitochondrial genotype. Eight studies of more than 2,500 volunteers identified that neurocognitive disorders also continue to be common, with diagnostic rates ranging from 25% to 69% and varying based on stage of disease, antiretroviral use, diabetes mellitus, and co-infections with hepatitis viruses. In addition to these findings from physical examination and cognitive testing of people living with HIV, new information from imaging and autopsy studies confirmed that injury of the brain is common in people with HIV. For example, blood flow to the brain in people living with HIV (PLWH) is similar to people who are 15-20 years older and do not have HIV and nearly 4 in 5 PLWH die with brain abnormalities. New findings on antiretroviral treatment (ART) of the nervous system indicated approaches that may improve these troubling findings. Studies identified that HIV in the nervous system may be better suppressed by selecting ART regimens based on better penetration characteristics and, in some cases, on resistance testing of HIV from cerebral spinal fluid (CSF). Together, the reports at the Conference confirmed that HIV continues to commonly injure the nervous system but they also provided hope for better methods of assessing and treating these important problems in people living with HIV.
Distal Sensory Peripheral Neuropathy (DSPN)
Table 1 summarizes the findings of the abstracts related to DSPN.
Changes in the epidemic may affect the occurrence and severity of distal sensory peripheral neuropathy (DSPN) in people living with HIV/AIDS. Many of the potentially influential changes link to the use of combination antiretroviral therapy (ART), including the substantial immune recovery that can occur, the advancing age of people whose survival has been extended by ART, and declines in the use of neurotoxic nucleoside reverse transcriptase inhibitors (e.g., the dideoxynucleoside analogues, stavudine and didanosine, which are sometimes referred to as d-drugs).
DSPN can be assessed by a clinician (e.g., signs observed on physical exam, nerve conduction studies, skin biopsy) and by the patient (e.g., symptoms of pain or numbness, impact on quality of life). Patient descriptions are very important for understanding how the disease affects daily life but clinician descriptions are essential for understanding the burden of the disease in our community. Ellis et al (abstract 461) used both approaches to describe the burden of DSPN in people living with HIV (PLWH), reporting on findings from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. This large cohort study enrolled 1,555 PLWH in 6 US cities (Seattle, San Diego, St. Louis, New York, Galveston, and Baltimore). Clinicians performed careful physical exams and obtained standardized medical histories to gather the information need to diagnose DSPN. 57% of the 1,555 PLWH had evidence of at least mild DSPN on physical exam (at least one abnormal clinical sign) and 38% of these people reported pain in their legs that was consistent with DSPN. Not surprisingly, the people who reported pain also had worse quality of life, when assessed with a standardized instrument (Medical Outcomes Survey). The study analyzed the correlates of DSPN, identifying that people with DSPN were older, had lower CD4+ cell counts in the past, were using ART, had used d-drugs before, and had a history of heroin abuse. In particular, people who were having pain were more likely to have used d-drugs and had lower CD4+ cell counts in the past. Findings from CHARTER were based mostly on PLWH who had used ART before but another study focused on PLWH who had never used ART when they first entered the study. Evans et al (abstract 462) studied 2,135 ART-naive PLWH followed longitudinally for up to 7 years. Everyone started a new ART regimen during the study and about 90% of them achieved undetectable viral loads within 48 weeks. 30% had evidence of at least mild DSPN on physical exam after 48 weeks of ART and this increased to 41% after 8 years even though d-drug use declined during the period of observation. Evidence of DSPN was again associated with older age and d-drug use as well as higher viral loads and lower CD4+ cell counts before treatment. Two important differences in this study are that few of the volunteers had painful symptoms (3 - 5%) and the impact on quality of life was not described. These two studies assessed two large and distinct cohorts but their findings were consistent: DSPN remains common and is associated with older age, d-drug use, and more advanced HIV disease. These findings suggest that earlier initiation of ART that does not include d-drugs may protect patients from neuropathy disability and improve quality-of-life.
Other reports at CROI further our understanding of DSPN. We know, for example, that DSPN occurs more commonly in the legs than the arms and one explanation for this is that longer nerves are more susceptible to injury. Because of this, taller patients may develop DSPN more commonly than shorter ones. Cherry et al (abstract 161) tested this hypothesis by comparing DSPN risk to several simple clinical indicators, including height, in 294 PLWH from Australia and southeast Asia. In addition to d-drug use, taller height and older age were associated with new onset DSPN. DSPN risk increased from 20% in younger, shorter patients to 33% in younger, taller patients, 38% in older, shorter patients and 66% in those older than 40 years and taller than 170 cm (about 5' 7") who received d-drugs.
The metabolic syndrome is a collection of risks for vascular disease like heart attack and stroke that is associated with aging and includes high cholesterol (dyslipidemia), high blood sugar (insulin resistance), and high blood pressure (hypertension). HIV infection and ART each appear to increase risk for the metabolic syndrome. Because components of the metabolic syndrome are known also to increase risk for polyneuropathy, some investigators have speculated that the metabolic syndrome may be one of the factors leading to persistent DSPN in CART-treated individuals. Ances et al. (abstract 463) evaluated this possibility in a subgroup of 130 subjects from the CHARTER cohort who had fasting measurements of blood glucose and triglycerides. For the purposes of these analyses, the metabolic syndrome was defined as having 3 or more of the following 5 risk factors: (1) high body mass index (BMI > 25 kg/m2), (2) hypertriglyceridemia (≥ 150 mg/dL), (3) low HDL-C (< 40 mg/dL for men and < 50 mg/dL for women), (4) hypertension (systolic ≥ 130 mm Hg, diastolic ≥ 85 mm Hg or use of anti-hypertensive medication, (5) hyperglycemia (≥ 110 mg/dL) or use of antidiabetic medication. While almost 1/3 of subjects met criteria for the metabolic syndrome and more than half had DSPN, the two were not associated. Among the metabolic syndrome components, only hypertriglyceridemia was significantly associated with DSPN. In a separate analysis of the larger cohort, diabetes mellitus, although uncommon, was significantly associated with an increase frequency of DSPN.
Existing treatments for painful neuropathy are only symptomatic, and investigators have long sought treatments that would enhance peripheral nerve regeneration and restore function, in addition to relieving pain. The type of DSPN that is linked to the neurotoxicity of d-drugs - as opposed to the DSPN that occurs in people living with HIV who have never taken d-drugs - probably results from mitochondrial "poisoning". While the use of d-drugs has declined in the North America and Europe due to the availability of alternatives, they are still widely prescribed in resource-limited settings because low-cost generic versions are available. Cherry et al (Abstract 447) reported on a neuroprotective treatment for d-drug DSPN, Co-enzyme Q10 (CoQ10; ubiquinone). CoQ10 is a component of the electron transport chain in mitochondria and participates in aerobic cellular respiration, which generates the vast majority of the body's energy. In the laboratory, growth of neurons was relatively preserved in the CoQ10-treated samples, despite the presence of d-drugs. Although CoQ10 is currently too expensive for widespread use in resource-limited settings, these data support continued investigation of CoQ10 and related compounds.
HIV-Associated Neurocognitive Disorders (HAND)
Table 2 summarizes the findings of the abstracts related to HAND.
The widespread use of ART has led to a decline in the more severe neurologic complications of HIV, such as HAD, but people living with HIV continue to experience mild and moderately severe forms of nervous system disease. The updated definition of HIV-associated neurocognitive disorders (HAND) has helped standardize reports from different regions of the world. This diagnostic approach defines asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND) as impairment in cognitive functioning that involves at least 2 cognitive abilities (e.g., learning, memory). MND and ANI are distinguished by their impact on everyday functioning with impairment occurring in MND but none in ANI.
In addition to the peripheral nervous system findings from CHARTER (above), investigators reported the central nervous system findings in the study's 1,555 volunteers as well (abstract 154). Similar to the population of many clinics in the US, the volunteers were mostly middle-aged (mean 43 years), men (77%) of color (61%) who had AIDS (63%), were taking ART (71%), and had substantial immune recovery (83% had CD4+ cell counts above 200/μL with an average of 460/μL). Even though most subjects were taking effective ART and had substantial immune recovery, a majority (53%) had cognitive impairment, performing poorly on tasks of learning, memory, and executive functioning (e.g., the ability to plan and initiate actions). Since many PLWH have other conditions that can affect thinking and memory (e.g., history of severe head injury, severe or intractable epilepsy or psychiatric disease, or severe or ongoing substance use disorders), the investigators carefully assessed these conditions and categorized volunteers into those who seemed to be affected or unaffected by these conditions. The majority (84%) did not have or did not seem to be severely affected by these conditions and, in this group, 47% still met criteria for cognitive impairment. Cognitive impairment was associated with the lowest ever CD4+ cell count (commonly called CD4 nadirs), detectable viral loads in blood, and the use of ART. In particular, volunteers whose CD4+ cell counts had never dropped below 200/μL and who were currently on ART with undetectable viral loads performed better than other volunteers, strongly arguing that earlier, effective ART prevents or treats HAND.
Important and confirmatory findings of the impact of HIV on the brain were reported from other countries. In an analysis of data from 107 volunteers of the French Neuradapt cohort, Vassallo et al (abstract 464) also reported that neurocognitive disorders were common. Similar to the CHARTER cohort, most volunteers in this study were ART-treated (86%) with viral loads in blood that were below 40 copies/mL and average CD+ cell counts of 527/μL. Despite this, 25% of participants were diagnosed with HAND (ANI 11%, MND 10%, HAD 4%) and the investigators identified an additional 44% who had impairment in one cognitive ability. The correlates of cognitive impairment in this group differed from CHARTER, though. Only co-infection with hepatitis C virus (HCV) was associated with worse thinking and memory. Another analysis from France identified links between cognitive impairment and another liver virus, hepatitis B virus (HBV). Bonnet et al (abstract 474) assessed 230 volunteers who had similar demographic and disease characteristics to the other cohorts and were enrolled in the ANRS CO3 Aquitaine cohort. This analysis focused on the diagnosis of MND, identifying the condition in 24% of the cohort, which is substantially higher than the prevalence identified in the CHARTER cohort (10%). In addition to HBV co-infection, MND was associated with older age and AIDS as well as lower levels of education and current unemployment.
The link identified between older age and worse neuropsychological performance confirms prior observations [Valcour et al JAIDS, 2006, 43: 405-10]. Since ART has improved survival, more and more people are living with HIV for many years. As this group reaches their 40s and 50s, their risk for cognitive impairment may be substantially higher than people who do not have HIV. Candidate mechanisms that might affect the aging brain of PLWH include accelerated neurodegeneration of the type that can occur with normal aging, disorders of amyloid (similar to Alzheimer's Disease), or vascular injury that can occur with metabolic disorders such as insulin resistance and dyslipidemia.
Because of reports of cognitive impairment becoming more common as PLWH age, a substudy of the Sigma cohort focused on people older than 60 (abstract 459). Brief neuropsychological testing identified that more than half (19 of 37, 51%) were impaired. The study also identified that more than two-thirds (25 of 37, 68%) had metabolic abnormalities, such as dyslipidemia, but they were not more likely to have cognitive impairment in this small study. The role of metabolic abnormalities was also examined in a substudy of CHARTER (abstract 458). Fasting blood sugar (glucose), insulin, and cholesterol were measured in 145 volunteers. The people in this substudy who had HAND were heavier, had worse cholesterol profiles (lower high density lipoprotein cholesterol and higher triglycerides), and were more likely to have diabetes, confirming that metabolic abnormalities seem to increase the risk for HAND.
Two studies reported other parts of the world. Robertson et al (abstract 485) reported on HIV-associated neurological disease from countries of Africa (Malawi, Zimbabwe), Asia (India, Thailand), and South America (Brazil, Peru). They identified that 29% had at least one neurological abnormality, including 6% with MND, 1% with HAD, 10% with "diffuse CNS disease", and 6% with "focal CNS disease". Ruel et al (abstract 920) evaluated cognitive function in African children, a group that has been understudied in recent years. The investigators evaluated 96 HIV-infected and 122 -uninfected children from Kampala, Uganda who were aged 3 to 12 years and enrolled in the Children with HIV and Malaria Project (CHAMP). The performance of HIV-infected children on several tasks was worse than uninfected children, indicating that the development of these children was delayed. Worse performance was associated with higher viral loads in blood but not worse CD4+ cell counts. These findings have important implications since, as the investigators indicate, few clinics have the resources to assess children for developmental delay and, in the absence of testing, the children in this study would not be eligible to receive ART based on current World Health Organization guidelines. Since these developmental delays may not be completely reversible, these findings argue for testing and early treatment of HIV-infected children with developmental delay or cognitive impairment.
Assessments of thinking and memory provide invaluable evidence of the impact of HIV on the brain during life but data from more direct observations of the brain, such as specialized imaging tests or brain tissue analyses, provide important validation. Magnetic resonance imaging (MRI) in the CHARTER study, for example, identified that cognitive impairment was associated with loss of brain tissue (atrophy of gray matter, the tissue that contains the cell bodies of neurons) and abnormalities of the remaining tissue (abnormal white matter, the tissue that contains the axons that conduct neuronal impulses) (abstract 154). Another large group investigating the relationships between cognition and brain imaging in the US, the HIV Neuroimaging Consortium, also presented findings at the conference, confirming that HIV-infected individuals had loss of brain tissue (abstract 480). The Consortium also evaluated PLWH with magnetic resonance spectroscopy, a method that can estimate the biochemistry of brain regions (Abstract 156), identifying evidence of inflammation in people with HIV and evidence of loss of neurons in people with HAND or with fatigue (abstract 479). A third study evaluated the impact of aging on blood flow to the brain by a version of a technique called functional MRI. Overall, people with HIV had worse blood flow to the brain that was similar to people who did not have HIV who were 15 to 20 years older.
The U.S. National NeuroAIDS Tissue Consortium studied the impact of HIV on the brain by directly evaluating brain tissue from nearly 600 people who had died with HIV/AIDS (abstract 155). One hundred nine (17%) people exhibited evidence of typical HIV-related brain pathology (HIV encephalitis, HIV leukoencephalopathy, or microglial nodules). Volunteers who died with evidence of HBP were less likely to be taking ART prior to death and had lower CD4+ cell count nadirs and higher viral loads in blood prior to death. Even though most brains did not have typical HBP, few were normal (22%). One hundred fifteen (20%) had evidence of a non-infectious disease and another 69 (12%) had minimal abnormalities that were not typical for another diagnosis. Substantial proportions of individuals had HAND (88%) or depression (60%) during their lives but neither of these conditions was associated with typical HBP. Instead, HAND, particularly the more severe HIV-associated dementia, was associated with another finding (type II Alzheimer gliosis), indicating a possible shift in the ways that HIV and ART injure the brain. Overall, these findings indicate that the prevalence of HBP has remained stable or decreased since the widespread use of combination ART but, despite this, other forms of brain disease are common with few people having normal-appearing brains by the time their disease reaches advanced stages.
Antiretroviral Therapy and the Nervous System
Penetration of ART into the nervous system has been an important focus of research in recent years, identifying that drugs that better penetrate into the nervous system result in better reductions of viral loads in CSF and greater improvements in cognitive impairment. Such research is limited by the inability to directly measure antiretroviral concentrations in brain tissue in humans, by the absence of drug concentration data in CSF for many antiretrovirals, and by the perceived clinical irrelevance of outcomes assessments (e.g., viral load assays, comprehensive neuropsychological testing, specialized imaging of the brain). Direct measurement of antiretroviral drug concentrations in brain tissue may best be accomplished in animal studies but human studies reported at the Conference extended work in the field by measuring drug concentrations in CSF and improving current assessment tools.
In another substudy of CHARTER, Best et al (abstract 702) measured efavirenz or emtricitabine concentrations in CSF. Efavirenz concentrations have been previously measured in CSF [Tashima et al, J Infect Dis 1999, 180(3): 862-4; Antinori et al, Clin Infect Dis 2005, 41(12): 1787-93] but the results were inconsistent, with one study finding low levels of efavirenz in CSF but the other finding none. Best et al initially found undetectable levels of efavirenz in CSF also but used an extraction method (methyl tert-butyl ether) to improve the sensitivity of the assay by an order of magnitude. Once they did so, they found that efavirenz concentrations were 0.5% of those in blood and exceeded the median inhibitory concentration in nearly all of the 80 CSF specimens that were assayed. Emtricitabine was much easier to detect in CSF (43% of the concentrations in blood) and exceeded the median inhibitory concentration in all 21 CSF specimens assayed. These results may explain the inconsistency in the published findings on efavirenz concentrations in CSF (i.e., additional steps are necessary in the laboratory to measure the low concentrations of efavirenz present in CSF) and identify that emtricitabine may be an excellent choice for controlling HIV in the nervous system.
In a separate substudy of CHARTER, Letendre et al (abstract 484a) used an assay capable of detecting HIV at very low levels (2 copies/mL) to more sensitively measure viral loads in CSF from 300 individuals when they were below 50 copies/mL with the most commonly used commercial assay. One hundred twenty-two (41%) had viral loads between 2 and 50 copies/mL in CSF and these individuals used ART regimens that had worse estimates of penetration into the nervous system. The more sensitive assay was also performed in 100 matched blood specimens from these 122 individuals, identifying that 26% had no detectable HIV in blood even though HIV was present in CSF. These individuals performed much worse on neuropsychological testing. These findings indicate that a substantial proportion of effectively treated individuals have persistent HIV in the nervous system and that this is associated with worse ART penetration and cognitive impairment. These findings also support that a more sensitive viral load assay may have value in managing HAND in the clinic.
Canestri et al (abstract 484a) also presented data supporting that ART is not effective in the nervous system in all treated individuals and that this can lead to neurologic abnormalities. The group identified 10 individuals who were on stable ART for a median of 14 months but had the new onset of acute or subacute neurologic abnormalities, such as symptoms of cognitive impairment, psychiatric disease, or meningitis. Even though viral loads were below 500 copies/mL in blood in all 10 patients, viral loads in CSF averaged 952 copies/mL and were more than 1 log10 copies/mL higher than in blood. Resistance testing was performed using HIV from CSF and ART was modified based on these results and on estimates of ART penetration into the nervous system. Treatment modification resulted in clinical improvement in all 10 patients and declines in viral loads in CSF to undetectable in 7. These data reinforce that ART can fail primarily in the CNS and identify a clinical approach that improves the effectiveness of treatment when this occurs.
One challenge to understanding the impact of ART on the brain is the rapidly expanding number of drugs available to patients and prescribers. One recent class of antiretrovirals, CCR5 antagonists, were designed to interfere with the use of this cell entry receptor by HIV. Two drugs in this category are either currently available or in development (maraviroc, vicriviroc) and physicochemical data indicate that both may penetrate into the CNS in therapeutic concentrations. The expression of CCR5 and HIV's other common co-receptor, CXCR4, varies by cell type. HIV viruses that infect macrophages and microglia, the cells that are productively infected in the brain, are more likely to use CCR5 than CXCR4. The combination of preferential use of CCR5 in the brain and good penetration of CCR5 antagonists suggests that this class of drugs may play an important role in treatment of the HIV-infected nervous system. This conclusion would be further supported if co-receptor usage assays indicated differences between HIV derived from the CSF and blood. Spudich et al (abstact 469) compared co-receptor usage and replication capacity in 18 chronically HIV-infected individuals using the Trofile assay (Monogram Biosciences, South San Francisco, CA USA), demonstrating that CCR5 usage was similar by HIV derived from CSF and blood but, when CXCR4 was used by blood-derived HIV, the relative usage by CSF-derived virus was less. This compartmentalization in co-receptor usage supports the argument of retained activity of CCR5 antagonists in the nervous system even when they may fail in blood.
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