Combination antiretroviral therapy begins to improve neuropsychological symptoms in HIV-positive patients several weeks after initiation of treatment and peaks between six and eight months later, using drugs that penetrate the CNS providing greater gains overall, according to a new study conducted at the University of California, San Diego (UCSD).
The Cognitive Intervention Trial provided several different analyses, variables, and statistical models to evaluate neuropsychological (NP) improvement in 37 patients with a range of HIV-associated neurocognitive disorders (HAND).
Untreated mild-to-moderate HAND patients and those beginning new regimens participated in a battery of NP tests at 12, 24, 36, and 48 weeks after starting combination antiretroviral therapy (CART). Clinically meaningful improvement was observed in 13 percent of patients within 12 weeks and in 40.9 percent by week 36, according to results published in the Aug. 4 issue of Neurology.
In multivariate analyses, unique predictors of improvement included more severe baseline NP impairment and higher CNS penetration, as measured by lower HIV viral levels in their CSF. Symptoms grew significantly worse in fewer than 5 percent of the treated subjects.
Patients who achieved CSF suppression, defined as a viral load (VL) of less than 50 c/mL, had better neurocognitive outcomes than did others with higher VL in the CNS, or those whose regimen did not include CNS-penetrating agents. High CNS-penetrating antiretroviral drugs include abacavir, zidovudine/3TC, delavirdine, amprenavir, indinavir, nevirapine, and stavudine/D4T.
Lead investigator Lucette Cysique, PhD, a clinical neuropsychologist at the University of New South Wales in, Darlinghurst, Australia, and her UCSD colleagues, noted that the beneficial effects of CSF-penetrating drugs on cognitive performance in such patients had been observed in only one other longitudinal study, and only in analyses using one variable.
Dr. Cysique told Neurology Today in a telephone interview that the findings help address two important issues with regard to NP and HIV-CART treatment. The first is the current paucity of reliable methods for monitoring NP improvement in HIV patients, and the second is whether CNS penetration is important in treating cognitive symptoms.
“Although our findings have to be replicated in larger randomized trials, we were able to detect when NP changes in many CART patients begin to take place and how long improvement may continue. But perhaps the most important finding was that patients receiving CNS-penetrating drugs had the most robust improvement,” she said.
RESULTS: VIRAL LOADS
Among 36 patients who had a detectible plasma HIV viral load at baseline of <50c/mL, levels could no longer be detected in 50 percent after 12 weeks and in 95 percent after one year. Among 34 patients with an available CSF viral load at baseline, 29 had undetectable levels after 12 weeks.
Plasma CD4 cell counts improved sharply at week 12 (p<0.0001) and more gradually thereafter, while the kinetics of the viral load in plasma and the CSF sharply improved at week 12 (p<0.0001), without significant changes at subsequent points.
“This study provides new evidence that choosing antiretroviral medications that reach therapeutic concentrations in the CNS may offer greater cognitive benefits,” she said. “And whether the initial NP improvement happened sooner or later, the magnitude of improvement was greatest in individuals who had lowest baseline performance.”
Nonetheless, improvements of lower magnitude were observed in participants with less impairment at baseline, with between 13.5 percent and 40.9 percent of patients showing some improvement across the study.
“The therapeutic implications of our study are twofold,” according to the authors. “HAND should be proactively monitored, and drug regimens with the estimated CNS penetration should be selected when possible, depending on treatment and toxicity histories and drug resistance testing.”
Both the CNS penetration-effectiveness (CPE) score (p=0.002) and baseline NP performance (Global Deficit Score (GDS) p=0.024) remained predictive of neurocognitive improvement, with lower CPE scores correlating with higher CSF viral loads.
“HAND should be proactively monitored, and drug regimens with the estimated CNS penetration — CPE scores greater than 2 — should be selected,” Dr. Cystique said.
She noted that while most neurologists are aware of NP changes in HIV patients and the potential for cognitive improvement with combination therapy, more primary providers need to be educated about CART and what NP changes may take place, when they will take place, and for how long.
“Our study was not large enough to provide the evidence needed for general practice, “ she said, “but it is a start and refocuses the question.”
AN UNRESOLVED ISSUE
Ned Sacktor, MD, associate professor of neurology at Johns Hopkins University School of Medicine, in Baltimore, MD, agreed the findings provide additional evidence that CNS penetrating CART drugs may yield greater and more rapid cognitive improvement in neuroAIDS patients, but the issue is far from resolved.
“The study is somewhat controversial vis a vis whether CNS penetration makes a difference in treating cognitive symptoms,” he told Neurology Today in a telephone interview.
“Some clinicians say yes, others no. This is another study suggesting the former,” commented Dr. Sacktor, whose research focuses on cognitive manifestations on HIV.
One “surprising” result in the study was that cognitive benefits continue for longer than has previously been reported, he said.
“In general, we assume that most cognitive improvement occurs in the first three months, but this suggests that improvements can continue for six or nine months.”
The Clinical Trial of CNS-Targeted HAART (CIT2) is currently under way and recruiting patients. The primary investigator is co-author Ronald J. Ellis, MD, at UCSD. For more information: http://clinicaltrials.gov/ct2/show/NCT00624195.