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This is your brain off drugs: the neurocognitive effects of treatment interruption
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CROI Feb 2007, Los Angeles
Written by David Margolis, MD, University of North Carolina
HIV gets into the CNS within days. In some, this leads to minor cognitive disorder and in even fewer leads to AIDS dementia. Some ARVs penetrate the CNS better than others. Many studies have shown neurocognitive improvement with HAART but neurocognitive impairment still occurs on HAART. In the ACTG ALLRT study of 1160 patients 26% had sustained impairment.
ACTG 5170 was a study in stable patients who had a CD4 count of 350 cells/ul or more prior to antiretroviral therapy (ART) initiation, HIV RNA < 55,000 copies/mL within 45 days of study entry, ART (≥ 2 drugs) for ≥ 6 months, and who desired to stop ART. Largely observational, patients were followed for 96 weeks after ART interruption. The primary results of the study were presented at CROI 2006, and will be published in JID soon. At baseline 71% of patient had VL<50 c/ml; median CD4 833 cells/ul; 14% <350 CD4, 59% 351-500 CD4, 27% >500 CD4; pre-ART viral load, median: 17% <400 - 5,000 c/ml; 36% 5,001 - 55,000 c/ml; 19% >55,000 c/ml; 28% not available). Median nadir CD4 count was 436 cells/ul, 86% nadir >350 cell/ul.
This study sought to define the safety of ART interruption, with the hope of better defining predictors of future stability off HAART, or groups in which TI should be avoided. ART was restarted at the discretion of the patient and health care provider. One hundred sixty-seven subjects (83% male) with median age of 42 yrs enrolled with a median nadir CD4 of 436mm3 and 4.5 median years on ART. After interruption the median CD$ count declined and HIV RNA increased. By week 96, 17 subjects had confirmed CD4 cell counts 250 cells/mm3 and 46 subjects had reinitiated ART. Twenty-nine subjects with HIV-1 RNA 400 copies/mL at study entry chose to reinitiate ART and stayed on ART for longer than 16 weeks. Twenty-four of these 29 subjects achieved HIV-1 RNA 400 copies/mL by week 16 of ART reinitiation.
While only a few HIV related clinical events occurred in study subjects who stopped ART, a CD4 nadir (lowest ever CD4 count) of below 400 cells/mm3 was associated with an increased risk of significant CD4 decline off ART and an increased likelihood that ART would be reinitiated within 2 years.
It was hypothesized that stopping ART would be associated with poorer neurocognitive function, and re-initiating HAART leads to improved neuropsychological performance. Neurocognitive dysfunction is associated with systemic disease in untreated HIV. Prior studies have shown improved neurocognition with initiation of ART. At CROI 2007, Robertson presented the results of a neurocognitive substudy of ACTG 5170. An average summary score (NPZ3) of the three neuropsychological tests (Digit Symbol, Trailmaking A and B) adjusted for demographic differences was computed. These tests assess psychomotor speed, attention, concentration, cognitive sequencing and shifting cognitive sets, all known to be altered by HIV. Mean NPZ3 scores increased while patients were off ART (increases of 0.22, 0.39, 0.53, 0.74 at weeks 24, 48, 72, and 96 respectively; all p-values<0.001). In analyses attempting to eliminate practice effects, significant increases in scores beyond week 48 were noted.
One would assume at first glance that this effect might be created by the discontinuation of efavirenz (EFV, Sustiva) in some patients suffering chronic, low-grade toxicity from this drug. However, no significant differences were noted when patients discontinuing EFV- and non-EFV-containing regimens were compared.
Further, in 46 patients that restarted ART prior to week 96, no significant changes in neurocognitive function were observed upon ART reinitiation. NPZ scores increased 0.06 in 37 patients at 24 week, increased 0.09 in 25 patients at 48 weeks, and decreased 0.06 in 10 patients at 72 weeks after restart of ART. None of these changes were quantitatively significant.
Reassuring, although somewhat surprising, the study could only conclude that patients with preserved immune function who discontinued ART did not experience decreases in neurocognitive function. Sensitivity analyses to adjust for practice effects and the selection bias of ART reinitiation do not completely explain this observation. Scores continued to improve after the 3rd visit, at which time test-taking practice effects would be expected to disappear.
Many studies have found that antiretroviral treatment improves neurocognitive functioning later in the disease. This study's findings do not refute the neurocognitive benefit of ART in advanced disease. The study is not sufficiently powered, nor appropriately controlled, to allow the suggestion that ART decreases neurocognitive function. Although the SMART study has demonstrated increased risk of clinical events in any patients that stop ART, this study is reassuring in that should healthy patients elect to stop ART early in disease, neurocognitive decline should not occur.
The presenter Kevin Robertson said there were a lot of study limitations: not randomized, subjects elected to come off ART/resume ART at any time. There was no control group. No internal reference to interpret the changes. And Robertson concluded the most we can conclude from this study discontinuing HAART in healthy subjects able to remain off therapy, no neurocognitive decline was detected, but perhaps we should conduct further randomized, controlled study of HAART toxicity on CNS function. For the resumption of HAART there was no significant change detected in neurocognitive scores possibly due to the limited sample size. Robertson said this study was in a unique cohort, this study does not suggest you should not take your HAART, in advanced disease ART improves neurocognitive function.
Notes from Jules Levin: In the Q&A after the talk, questions included how many patients were on efavirenz, and Robertson said we have this data but didn't know the answer right now. A second question asked if they looked at drugs that had good CNS pentration vs those that did not? Robertson said he thought there were more than 20 different regimens patients were taking, we haven't gone back to figure a CNS penetration score but this was an interesting idea & something they could do, and this is something of great interest. In response to a third question, Robertson said they did not look at patterns or changes in patients taking sleep agents or psychotropics, and Robertson said this would be a good idea to look at. Another question that perhaps patients felt less depressed after stopping HAART so perhaps they were glad to have stopped HAART, so did they look at depression scores. Robertson said they collected quality of life data and are starting to examine that now. Another questioner suggested that perhaps the study did not use a broad enough battery of tests to fully analyze neurocognitive function, to which Robertson said they had limitations in how much they could do.
So after interruption, CD4 declined and HIV RNA increased. I think if different types of patients were observed results might have been different . For patients with cognitive dysfunction before going HAART stopping ART dysfunction might have returned. For patients with lower nadir CD4s cognitive dysfunction might have occurred. For patients who had CD4 declines to low levels and/or high viral load after stopping HAART cognitive dysfunction might have occurred. This study was however as they said in what appeared to be a unique patient population who appeared healthy with high nadir CD4s.
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