The goal of this study was to determine if patients who begin or change to an ARV regimen with “good” CNS penetration, defined as a CPE rank ≥ 2, have better CSF virologic and neurocognitive outcomes than individuals who are not prescribed such regimens. Our study population was chosen to have advanced disease to increase the number of subjects with cognitive impairment, and, as expected, we found that subjects with neurocognitive impairment had lower median peripheral blood CD4+ T cells.
We found that regimens with CPE rank ≥ 2 conveyed greater odds of suppression of CSF HIV RNA. Use of an NNRTI-based regimen was not significantly related to the odds of suppression of CSF HIV RNA. No significant relationship between CPE rank and suppression of plasma HIV RNA was seen. This finding suggests that the benefit of CNS penetrating agents on suppression of CSF viral replication may be independent of the overall efficacy of a regimen. The findings in our longitudinal study are in agreement with those of a cross-sectional study [8
We also found that subjects who were ARV naïve had significantly greater odds of suppression of CSF virus compared to experienced subjects, even taking into account CPE rank or number of ARVs in a regimen. A longitudinal study of 29 individuals who started or changed cART also found that being ARV naïve predicted greater decline in CSF HIV RNA [10
In contrast to our hypothesis that subjects who were prescribed ARV regimens with good CNS penetration would have better neurocognitive performance, we found the opposite. In univariate analysis of NPZ4, compared to use of a regimen with CPE rank < 2, use of a regimen with CPE rank ≥ 2 was significantly associated with poorer neurocognitive performance in subjects who were cognitively impaired at study entry. The magnitude of the effect was substantial. In the same analysis, use of ARV regimens that contained more drugs was also significantly associated with poorer neurocognitive performance, although the magnitude of the effect was smaller. In multivariate analyses, CPE rank ≥ 2 remained significantly associated with poorer NPZ4 scores over the course of the study.
Previous studies have shown that neuropsychological test performance in HIV-infected individuals improves with repeat testing, consistent with a practice effect [9
]. Among subjects who were neuropsychologically impaired at study entry, we saw significant improvement in NPZ4 in subjects who were prescribed regimens with CPE rank < 2 and a trend toward improvement in those prescribed 3 agents (instead of 4). In contrast, we saw no significant change in performance in the subjects prescribed a regimen with CPE rank ≤ 2 or who were prescribed 4 drugs. Thus we cannot say that the latter group simply “improved less” than the former group.
At first inspection, our findings seem to be inconsistent with previous studies. For example, the incidence of HIV-associated dementia has significantly decreased in the era of cART [15
]. Although few studies have examined change in neuropsychological function after starting or changing ARV therapy, cognitive improvement has been documented, even when the regimen would not be considered “potent” [9
Nonetheless, the observation that neurocognitive impairment may be associated with specific components of a cART regimen is not without precedent. For example, a longitudinal study showed that patients whose ARV regimens contained ritonavir with another protease inhibitor or a regimen that contained ≥ 3 CNS penetrant drugs had poorer motor performance than patients who did not receive the protease inhibitor combination or who were prescribed regimens with < 3 penetrant drugs [19
]. The authors suggested that complex drug interactions could contribute to CNS toxicity. A proton magnetic resonance spectroscopy (MRS) study showed that subjects who took didanosine or stavudine had decreased frontal white matter N-acetyl aspartate concentrations compared to HIV-uninfected controls [20
]. This difference was not seen in patients who took zidovudine and lamivudine compared to controls. The authors speculated that the negative effect could be mediated by mitochondrial toxicity of didanosine and stavudine, a known effect of these drugs in the peripheral nervous system.
Several explanations could be advanced to explain our findings regarding the relationship between neurocognitive performance, number of ARV agents in a regimen, and measures of CNS drug penetration. First, the findings could be spurious. We limited our analysis of neurocognitive performance to subjects with abnormal performance at study entry to eliminate a “ceiling effect.” As a consequence, small numbers limited our analyses.
Poorer adherence to treatment, and hence untreated or poorly treated HIV, which we know is associated with poorer cognitive function, could also be raised as a possible explanation for why subjects who were prescribed CNS penetrant agents or a higher number of agents had poorer neurocognitive performance. We did not specifically address adherence, but plasma HIV RNA is a good surrogate for adherence. As in the group as a whole, in the subgroup of subjects included in the neurocognitive analyses, we did not see a relationship between number of ARV agents in a regimen or CPE rank and suppression of plasma HIV RNA (data not shown). These findings suggest that suboptimal adherence to treatment does not explain poorer cognitive performance. Similarly, the lack of association between number of drugs in a regimen and suppression of plasma HIV RNA argues against the possibility that subjects who took more ARVs did so because they had less well controlled HIV.
Subjects who took regimens that contained more drugs may have had more drug-related side effects, which could have impacted their cognitive performance. This possibility is particularly relevant to use of efavirenz, which has known cognitive adverse effects. However, we found no significant relationship between use of efavirenz and neuropsychological performance over the course of the study.
Our study has limitations. We assume that, because it takes into account virologic and pharmacologic data, the CPE score reflects CNS drug penetration rather than simply CSF drug penetration. We were unable to directly test this hypothesis, as we did not have access to pre- or postmortem brain tissue. We were not able to include data from 22 of the 101 enrolled subjects. However, our study population is, to our knowledge, the largest of any longitudinal investigation of subjects beginning or changing ARV therapy. Antiretroviral regimens were not randomly allocated, and were chosen by the treating provider or by the co-enrolling clinical trial. It is thus possible that subjects who were enrolled from clinical care and who were more cognitively impaired may have been preferentially prescribed a more penetrant regimen. Our finding that there was no significant relationship between cognitive impairment at baseline and the CPE rank of the initially prescribed regimen does not support this hypothesis. Another possibility is that highly experienced subjects may have been more likely to be cognitively impaired and to have received more ARV agents. However, we found that among those subjects with baseline NPZ4 ≤ -0.5, there was no significant difference in baseline NPZ4 score in experienced compared to naïve subjects. Similarly, there was no significant difference in the number of ARV agents prescribed experienced compared to naïve subjects over the course of the study. Nonetheless, confounding could have occurred based on subject characteristics that were not measured in the study.
Finally, it is possible that agents with good CNS penetration are neurotoxic in the population of subjects with advanced HIV. A mechanism for neurotoxicity is a matter of speculation. Patients with advanced disease might be more susceptible to drug-related neurotoxicity because of disruption of the blood-brain-barrier or because of decreased cognitive reserve due to chronic brain HIV infection or comorbidities such as age or vascular disease.
On a practical basis, our data support the contention that ARV regimens with estimated good CNS penetration are more effective than regimens with poorer CNS penetration in controlling CSF (and presumably CNS) viral replication, regardless of the number of agents in a regimen and whether the regimen is NNRTI-based or not. However, we are not able to say that better CNS penetration translates into better cognition. In fact, our data suggest that the opposite may be true. Our results should be interpreted in light of the limitations of the study. A larger, controlled trial that addresses the impact of CNS penetrant ARV regimens on cognition is required.