ARTICLE IN BRIEF
In a study of HIV patients, researchers found that those with asymptomatic neurocognitive impairment (ANI) at baseline had double the risk of being diagnosed with symptomatic HIV-associated neurocognitive disorders compared to those who had not previously been diagnosed with ANI.
Although so mild as to be unnoticed by HIV-positive patients, neurocognitive deficits detectable only upon testing significantly raise the risk — by two- to six-fold, depending on the measure — of later being diagnosed with symptomatic dysfunction, a large multicenter study has found.
The report from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group effectively settles the debate over whether asymptomatic impairments are cause for concern in people with HIV, researchers reached by Neurology Today agreed.
“Many practitioners thought the very idea of asymptomatic impairment just didn't make sense,” said Kevin Robertson, PhD, professor of neuropsychology and director of the AIDS Neurological Center at the University of North Carolina at Chapel Hill. “Others, including me, felt it was a valid category and that it would increase the risk of developing symptomatic deficits. But nobody had really proven it in a rigorous way. The CHARTER study validates the category and is a wake-up call to the field to start screening individuals and making sure that those who have asymptomatic neurocognitive impairments are carefully followed and offered the best available treatment.”
Dr. Robertson added: “It's a seminal paper and a major finding.”
A commentary accompanying the paper in the journal Neurology called the study “definitive.”
While agreeing that the study was well designed and its findings important, others cautioned that the cause of the neurocognitive dysfunction in people with HIV remains uncertain and perhaps multifactorial. In fact, a study by Dr. Robertson published in the journal Neurology in 2010 suggested that antiretroviral therapy (ART) may contribute in some way to the cognitive dysfunction; stable patients whose therapy was temporarily interrupted saw significant improvement in their neurocognitive status. Another study, also to be published in Neurology, found that antiretroviral therapy that greatly penetrates the CNS substantially increases the risk of HIV dementia.
“The key thing we still don't know, when someone presents with mild abnormalities on neuropsychological testing, is whether those deficits are directly caused by the ongoing HIV infection or whether there are other contributing factors,” said Ned Sacktor, MD, professor of neurology at Johns Hopkins University Medical Center. “Hepatitis C, depression, or substance abuse could also be causative factors.”
Dr. Sacktor participated in the CHARTER group as part of the Hopkins study site but was not involved in either the analysis or the writing of the paper published in Neurology.
With six sites in all, the CHARTER study involved 347 people with HIV, including 226 neurocognitively normal individuals and 121 with asymptomatic neurocognitive impairment (ANI) at baseline, diagnosed on the basis of performance on a test battery covering motor function (perceptual-motor speed), verbal fluency, executive function, attention/working memory, speed of information processing, learning, and memory. All patients underwent a psychiatric exam, assessment of daily functioning on the basis of self-report, and performance-based measures of daily functioning.
After a median follow-up of 45.2 months, during which neurocognitive assessments occurred approximately every six months, patients who had ANI at baseline had double the risk of being diagnosed with symptomatic HIV-associated neurocognitive disorders (HAND) compared to those who had not previously been diagnosed with ANI (CI: 1.1 – 3.6; p= 0.02), based on their own self-report. However, based on objective performance-based measures of daily functioning, the adjusted risk ratio for progressing to HAND for those with ANI was 5.8 (CI: 3.2 – 10.7; p<0.0001). For either self-report or performance-based measure, the adjusted risk ratio was 3.2 (CI: 2.0–5.0; p<0.0001).
Although antiretroviral regimen, virologic suppression, and substance abuse or dependence were not significant time-dependent covariates, both the current CD4 level and depression were, the study found.
“Although modern treatment for HIV has prolonged lives and markedly reduced medical complications, these neurocognitive impairments have been reported in about 40 percent of patients, and rates are elevated even in those who are receiving very good care,” said the first author of the study, Igor Grant, MD, distinguished professor and chair of the department of psychiatry and director of the HIV Neurocognitive Research Program at the University of California, San Diego.
“The controversy has been that if you need sophisticated tests to detect ANI, why bother?” said Dr. Grant. “Maybe it didn't matter. Now we've shown that it does, because patients with ANI are more likely to develop problems later on. The implication is we should at least be monitoring these people. Antiretroviral therapy is associated with better cognitive function, but there is now some evidence that those drugs that are better at getting into the CNS are more neurotoxic.”
Serena Spudich, MD, associate professor of neurology at the Yale School of Medicine, agreed with both Dr. Robertson and Dr. Sacktor that the continuing HIV infection itself is not necessarily the cause of the cognitive deficits. She has previously published papers suggesting that neurologic injury early during primary HIV infection, or that HIV escape into cerebrospinal fluid, are each associated with neurologic dysfunction.
“I would be careful not to conclude from this paper that in well-treated, ART-adherent patients, there is definitely a progressive disease in the CNS due to HIV itself,” she said in an email. She noted that at baseline, less than 75 percent of patients in both arms of the CHARTER study were on ART, and that the number of patients with undetectable viral loads was less than 50 percent.
“This issue of transition from ANI to mild neurocognitive disorder is not as clearly defined for people who are fully suppressed on ART,” she said. “This is a big question in the field for both HIV-infected patients and their providers.”
Dr. Spudich even questioned whether the transition from ANI to mild symptomatic deficits means that the neurocognitive disease is progressing. “Can it just be a recognition of a stable deficit?” she asked. “The use of self-report especially confuses things. The more objective testing helps get around this somewhat, though there are no norms for these performance-based tests.”
Even so, she emphasized, “In a way, the practical outcome is the same — HIV-infected patients who have asymptomatic neurocognitive impairments at baseline may indeed be at higher risk and need to be monitored and followed, even if their progression is not due to HIV itself.”
Presently no medication has yet been shown to forestall neurocognitive deficits in people with HIV, but two studies presented at meetings this year suggest possible interventions.
The first, presented in March at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, found that CSF markers of inflammation declined significantly in 49 sedentary, ART-treated patients who did one hour of brisk walking, with or without circuit training exercise, three times weekly for 12 weeks. However, the reduction was found only for the 25 patients who completed the program and had inflammatory marker data available.
Despite the study's limitations, Dr. Robertson said, “CSF markers of inflammation are thought to underlie the damage that occurs in the brain. There was a huge amount of excitement about that study. It has led the AIDS clinical trial group at the National Institute of Allergy and Infectious Diseases to consider assembling an exercise-focused group to look at whether a formal clinical trial should examine the effects of physical exercise.”
Another trial, to be presented in July at the 20th International AIDS Conference in Melbourne, involves 40 HIV-AIDS patients diagnosed with either ANI or mild neurocognitive disorders at the study's outset. According to the abstract, those randomized to undergo 36 sessions of computerized cognitive exercises over the course of three months no longer met the criteria for either ANI or MND at the study's conclusions, whereas the control group showed no change.
EXPERTS RESPOND TO DATA ON ASYMPTOMATIC IMPAIRMENTS IN PEOPLE WITH HIV
•. Grant I, Franklin DR Jr., Deutsch R, et al. for the CHARTER Group. Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology. 2014; Epub 2014 May 9.
•. Albert SM, Martin EM. HIV and the neuropsychology of everyday life. Neurology. 2014; Epub 2014 May 9.
•. Robertson KR, Su Z, Margolis DM, et al. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology. 2010; 74:(16): 1260–6.
•. Peluso MJ, Ferretti F, Peterson J, et al. Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS. 2012; 26:(14): 1765–74.
•. Peluso MJ, Meyerhoff DJ, Price RW, et al. Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. J Infect Dis. 2013; 207:(11): 1703–12.
•. Longo V, Bonato M, Bossolasco S, et al. Brisk walking improves inflammatory markers in cART-treated patients. Abstract 763. CROI 2014. March 2014, Boston.
•. Livelli A, Pia L, Orofino G, et al. Cognitive rehabilitation treatment in HIV/AIDS patients with asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorders (MND). 20th International AIDS conference, Melbourne. http://bit.ly/ANI-HIV