Changes in Cognition During Antiretroviral Therapy
Changes in Cognition During Antiretroviral Therapy
Objective: Although HIV-associated neurocognitive disorders should be treated with highly active antiretroviral treatment (HAART) regimens with good central nervous system (CNS) penetration, the definition of neuroactive HAART remains controversial. We compared 2 ranking systems to measure HAART neuroeffectiveness.
Methods: Patients with (n = 93) or at risk for (n = 92) HIV-associated neurocognitive disorders underwent neuropsychological (NP) test batteries before HAART initiation and at follow-up. Changes in normatively adjusted summary NP test z scores were calculated for each subject. Two neuropenetration scores were calculated: the central nervous system penetration reference score (number of drugs in the combination among zidovudine, abacavir, stavudine, lamivudine, efavirenz, nevirapine, indinavir, and lopinavir-ritonavir) and the CNS penetration-effectiveness (CPE) score: a summary score of 1 (high: zidovudine, abacavir, nevirapine, amprenavir-ritonavir, atazanavir-ritonavir, indinavir-ritonavir, and lopinavir-ritonavir), 0.5 (intermediate: stavudine, lamivudine, emtricitabine, efavirenz, amprenavir, atazanavir-ritonavir, and indinavir), and 0 (low penetration: remaining antiretrovirals) for each drug in the combination. Main outcome measures were changes in global NPZ scores and in summary z scores on 5 domains.
Results: At regression analyses, higher CPE scores correlated with greater improvements in NPZ-4 (P = 0.0283), NPZ-8 (P = 0.0071), concentration and speed of mental processing (P = 0.0046), and mental flexibility (P = 0.0262) summary z scores. The correlation was stronger among NP-impaired patients. By contrast, higher estimates of neuroeffectiveness with the alternative system showed no correlation. No association was seen between CD4 and plasma viral load changes with both scores.
Conclusions: The CPE score represents a step forward toward the identification of a clinically useful approach to estimating HAART ability to improve cognition.
The HIV-associated neurocognitive disorders (HAND) are regarded as a direct manifestation of HIV-1 infection of the central nervous system (CNS). They are characterized by acquired impairment in cognitive functioning, disturbances in memory, attention, processing speed, and fine motor functions. Neuropsychologically, there is a characteristic impairment in psychomotor speed, memory, and sustained attention, and neuropsychological (NP) test batteries have been routinely included as primary outcome criterion to monitor neurological response to highly active antiretroviral treatment (HAART) in most published trials. The optimal treatment for HAND has not been established, but there is strong evidence that HAART can improve the cognitive dysfunction. The general consensus is that the ability of antiretroviral (ARV) drugs to reach the CNS is a critical factor for patients' neurological response. Several ARV drugs have been shown to be more neurologically active than others on the basis of their capacity to reduce cerebrospinal fluid (CSF) HIV RNA to undetectable levels and improve cognition. Moreover, it has been shown that virologic suppression in the CSF is associated with significant NP improvement. However, although HAND should be treated with ARV drugs with good central nervous system penetration (CP), how to identify a neuroactive HAART regimen remains controversial. A number of cross-sectional and prospective studies have investigated the effects of neuroactive HAART regimens on CSF viral load (VL) and on cognitive functions. In almost all published studies, zidovudine, stavudine, abacavir, lamivudine (3TC), indinavir, efavirenz, and nevirapine were considered ARV drugs with good CP, generally on the bases of their CSF concentration from human studies. CSF is closer to the brain parenchyma than any other body fluid, and CSF ARV drug concentration is relatively easy to measure. However, CSF drug concentration can vary widely between individuals. Moreover, how well CSF drug concentration reflects drug concentration within the brain parenchyma is unclear. Clinical studies are confined to examining drug concentration in human CSF, and we know little about brain penetration of ARV drugs. Recently, when trying to develop a clinically useful approach to estimating CNS effectiveness, the CHARTER Study Group proposed a new ranking system based not only on CSF drug concentration but also on the chemical properties of ARV drugs and on clinical studies on drug ability to reduce CSF VL and improve cognition. For these reasons, we evaluated changes in cognition during HAART as a function of 2 different scoring systems to measure ARV drug efficacy in treating HAND: the CP reference score derived from the existing literature and the CNS penetration-effectiveness (CPE) score proposed by the CHARTER Study Group. We hypothesized that neuroeffectiveness as calculated with the CPE CHARTER score could be more likely to show an association with changes in NP performance than the alternative CP reference score.
Abstract and Introduction
Abstract
Objective: Although HIV-associated neurocognitive disorders should be treated with highly active antiretroviral treatment (HAART) regimens with good central nervous system (CNS) penetration, the definition of neuroactive HAART remains controversial. We compared 2 ranking systems to measure HAART neuroeffectiveness.
Methods: Patients with (n = 93) or at risk for (n = 92) HIV-associated neurocognitive disorders underwent neuropsychological (NP) test batteries before HAART initiation and at follow-up. Changes in normatively adjusted summary NP test z scores were calculated for each subject. Two neuropenetration scores were calculated: the central nervous system penetration reference score (number of drugs in the combination among zidovudine, abacavir, stavudine, lamivudine, efavirenz, nevirapine, indinavir, and lopinavir-ritonavir) and the CNS penetration-effectiveness (CPE) score: a summary score of 1 (high: zidovudine, abacavir, nevirapine, amprenavir-ritonavir, atazanavir-ritonavir, indinavir-ritonavir, and lopinavir-ritonavir), 0.5 (intermediate: stavudine, lamivudine, emtricitabine, efavirenz, amprenavir, atazanavir-ritonavir, and indinavir), and 0 (low penetration: remaining antiretrovirals) for each drug in the combination. Main outcome measures were changes in global NPZ scores and in summary z scores on 5 domains.
Results: At regression analyses, higher CPE scores correlated with greater improvements in NPZ-4 (P = 0.0283), NPZ-8 (P = 0.0071), concentration and speed of mental processing (P = 0.0046), and mental flexibility (P = 0.0262) summary z scores. The correlation was stronger among NP-impaired patients. By contrast, higher estimates of neuroeffectiveness with the alternative system showed no correlation. No association was seen between CD4 and plasma viral load changes with both scores.
Conclusions: The CPE score represents a step forward toward the identification of a clinically useful approach to estimating HAART ability to improve cognition.
Introduction
The HIV-associated neurocognitive disorders (HAND) are regarded as a direct manifestation of HIV-1 infection of the central nervous system (CNS). They are characterized by acquired impairment in cognitive functioning, disturbances in memory, attention, processing speed, and fine motor functions. Neuropsychologically, there is a characteristic impairment in psychomotor speed, memory, and sustained attention, and neuropsychological (NP) test batteries have been routinely included as primary outcome criterion to monitor neurological response to highly active antiretroviral treatment (HAART) in most published trials. The optimal treatment for HAND has not been established, but there is strong evidence that HAART can improve the cognitive dysfunction. The general consensus is that the ability of antiretroviral (ARV) drugs to reach the CNS is a critical factor for patients' neurological response. Several ARV drugs have been shown to be more neurologically active than others on the basis of their capacity to reduce cerebrospinal fluid (CSF) HIV RNA to undetectable levels and improve cognition. Moreover, it has been shown that virologic suppression in the CSF is associated with significant NP improvement. However, although HAND should be treated with ARV drugs with good central nervous system penetration (CP), how to identify a neuroactive HAART regimen remains controversial. A number of cross-sectional and prospective studies have investigated the effects of neuroactive HAART regimens on CSF viral load (VL) and on cognitive functions. In almost all published studies, zidovudine, stavudine, abacavir, lamivudine (3TC), indinavir, efavirenz, and nevirapine were considered ARV drugs with good CP, generally on the bases of their CSF concentration from human studies. CSF is closer to the brain parenchyma than any other body fluid, and CSF ARV drug concentration is relatively easy to measure. However, CSF drug concentration can vary widely between individuals. Moreover, how well CSF drug concentration reflects drug concentration within the brain parenchyma is unclear. Clinical studies are confined to examining drug concentration in human CSF, and we know little about brain penetration of ARV drugs. Recently, when trying to develop a clinically useful approach to estimating CNS effectiveness, the CHARTER Study Group proposed a new ranking system based not only on CSF drug concentration but also on the chemical properties of ARV drugs and on clinical studies on drug ability to reduce CSF VL and improve cognition. For these reasons, we evaluated changes in cognition during HAART as a function of 2 different scoring systems to measure ARV drug efficacy in treating HAND: the CP reference score derived from the existing literature and the CNS penetration-effectiveness (CPE) score proposed by the CHARTER Study Group. We hypothesized that neuroeffectiveness as calculated with the CPE CHARTER score could be more likely to show an association with changes in NP performance than the alternative CP reference score.