Findings from this study show that for some persons with HAND initiating CART, cognitive improvement happens soon after initiation (13% at week 12), but more often 24, 36, and 48 weeks after initiation (up to 41%). In addition, whether the initial NP improvement happens sooner or later, the magnitude of improvement was greater in individuals who had the lowest baseline performance, although improvement of lesser magnitude was observable in less impaired participants at baseline (). This does not appear to be an artifact of regression to the mean because the latter should be controlled by the MS-Reg-CS methodology. Indeed, the regression change scores were derived from a normative sample from which no NP change was expected beyond practice effect or statistical artifact such as regression toward the mean. In other words, the “normed” definition of NP change in the CIT sample was exclusive of these confounds. Moreover, the pattern of NP change in the impairment subgroups () cannot be explained on the basis of regression to the mean because the least impaired subgroup does not show the lowest amount of improvement.
NP improvement was associated with decreasing plasma HIV viral load (but not CSF, potentially due to a lack of data variability by week 12 as detailed below), whether HIV viral load was treated as a continuous or dichotomous variable, and the effect was strongest at 24 and 48 weeks after CART initiation. This result is in accordance with previous studies.1,4
However, in the multivariate model that also includes baseline NP impairment, plasma viral load does not remain a unique contributor. Several mechanisms to explain NP improvement have been proposed in the literature. First, CART reduces HIV replication in the brain (as well as the blood).4
As a result, circulating activated monocytes are reduced, leading to a reduction of their migration into the brain and a resulting further reduction of HIV in the CNS.23
With a reduction of HIV and activated monocytes, neuroinflammation and production of neurotoxins is also reduced.24
The CPE score (greater than 2), for the participants’ CART regimens, was the other predictor of NP improvement in our multivariate analyses. The beneficial effect of CSF penetrating drugs has been observed in one other longitudinal study but only in univariate analyses.25
It was observed also over one time point in the subanalysis of this sample.4
Not only is this finding the first robust extension of the long-term beneficial effect of CART with better CNS penetration, our change score method and mixed effect modeling also yielded a specific magnitude of NP improvement of 2.46 units on average per 12-week period. This represents a large improvement arguably supporting a non-negligible effect of this factor and provides valuable information for future clinical trials. Better CART CNS penetration likely leads to more neurocognitive improvement because it better suppresses CNS viral replication.26
However, we were not able to show the latter. Potential reasons are that CSF viral load may only imperfectly reflect the state of HIV replication in the brain, that currently available viral load assays are not sufficiently sensitive for CSF, and that secondary effects of CART, such as reduction in mediators of neuroinflammation, may be important in neurocognitive recovery. Perhaps the most likely explanation is related to the data variance, as we found that 80% of subjects suppressed CSF viral load at week 12. This leaves only 20% detectable, a very small subgroup. Thus the categorical analysis of CSF viral suppression was probably not powered to demonstrate the expected effect. By comparison, proportions remaining detectable and undetectable at week 12 for plasma were better balanced, providing more power.
The therapeutic implications of our study are twofold: 1) HAND should be proactively monitored; and 2) to minimize impact of HAND on productivity and life quality, drug regimens with the estimated CNS penetration (CPE scores greater than 2; see reference 22
for details) should be selected when possible based on treatment and toxicity histories and drug resistance testing. Adherence to CART presumably also is critical to improving cognitive functions, and may improve with better cognition.27
Since reported levels of treatment adherence were high in this study as compared to those observed in clinical practice, extra measures to promote good adherence, especially initially, may be needed for impaired patients to achieve results similar to ours.
Our study detected continuing improvement up to 1 year after a change in therapy. This supports findings of long-term observational cohorts demonstrating benefit of CART up to 3 years18,28
and even in patients with immune reconstitution syndrome up to 5 years.29
This suggests that the window for recovery of HIV-related brain injury may be relatively long.
Two findings from this study differed from those which were reported in our prior analysis of the CIT data.4
First, we did not find that CSF viral load was significantly associated with NP improvement. Secondly, we did not confirm that ART naive (38%) participants were more likely to improve. We believe that these differing findings result from different analytic approaches, and the inclusion of all study timepoints. Also, the initial study measured cognitive changes with the GDS, a measure that ignores changes within the normal range. For the current analysis, we used scaled scores which encompass the full range of performance, capturing not only return to normal, but also return to best levels of functioning. Moreover, the prior study found that higher CNS penetration was associated with better CSF viral load suppression, but not with better neurocognitive performance. This may have resulted from the use of updated estimates of CNS penetration based on data published after 2004 in the present study, as well as better estimate of NP change.
We believe that our current approach provides a more sensitive and yet stricter estimate of cognitive improvement when compared to the published literature. Indeed, the standardized change scores for expected NP change which were derived from a demographically comparable group of HIV− and clinically stable HIV+ participants correct for practice effects, regression toward the mean, and normal test-retest variation. These measures are more likely to reflect the “true” NP improvement without these sources of error (see legend).
Several limitations to our study should be recognized. First, our small sample size may have limited detection of less robust contributions to improvement by some of our predictors. Larger longitudinal studies with strategies to reduce attrition are needed. Secondly, the battery of tests ideally would have been larger. However, we found that our limited battery was highly correlated to the original GDS derived from more comprehensive NP evaluations.4
Still, when using this prorated battery, a number of important cognitive functions known to be affected by HIV infection and effective CART were not represented (e.g., learning, memory, executive functions). Finally, we used two sets of regression equations to compute the MS-Reg-CS for four time periods (baseline–12 weeks, 12–24 weeks, 24–36 weeks, 36–48 weeks). These equations may not account for some of the practice effects in our study at week 36 and 48. However, several studies indicate that practice effect most substantially applies to the second assessment and is greatly diminished with subsequent tests.17
The ideal design would have been to have a reference sample of comparable individuals tested at the exact same times as our participants. This highlights the need for normative data for NP change at various intervals relevant to clinical trials. Finally, we did not explore how cognitive improvement translated into potential everyday functioning. Future studies should aim at defining to what extent everyday functioning measures covary with NP change.