In the era before combination antiretroviral therapy (cART), several studies [1,2] showed that cerebrospinal fluid (CSF) HIV RNA levels correlated with the severity of HIV-associated dementia. In individuals with advanced HIV, CSF HIV RNA concentration correlated with neuropsychological test performance [3,4], and elevated HIV RNA levels in CSF predicted future cognitive impairment . Since the advent of cART, these relationships may be less robust [5,6], perhaps because many patients who receive cART achieve undetectable CSF HIV RNA concentrations or because CSF virus may be suppressed even in patients who are failing a cART regimen .
An ongoing question of particular interest is whether cART regimens that include agents that penetrate the central nervous system (CNS) in therapeutic concentrations reduce CSF virus and improve neuropsychological test performance. These questions have been addressed in several cross-sectional and prospective studies , but limited research has been conducted on individuals who begin or change treatment [9,10]. We report the results of AIDS Clinical Trials Group study number 736, a multisite longitudinal natural history study whose primary goals were to examine changes in CSF and plasma HIV RNA, and in neuropsychological function, in HIV-infected individuals who begin or change a cART regimen.
Participants were required to have either a peripheral blood CD4+ T cell count of less than 200 cells/μl with plasma HIV RNA of more than 2000 copies/ml or plasma HIV RNA of more than 50 000 copies/ml regardless of CD4 cell count. All participants were either initiating a new cART regimen or changing an existing regimen because of virologic failure. A cART regimen was defined as containing at least three antiretroviral agents. The drug regimen was chosen by the participant's primary provider or, if the participant was enrolling into a treatment trial, by the randomization arm. The study protocol was reviewed and approved by the Institutional Review Board at each participating site. Human experimentation guidelines of each site were followed in the conduct of this research.
Within 21 days before beginning or changing the cART regimen, participants underwent a structured medical history and neurological examination, venipuncture and lumbar puncture, and neuropsychological tests. At all sites, participants underwent a brief neuropsychological test battery that included timed gait, grooved pegboard with the dominant hand, digit symbol, and finger tapping with the nondominant hand (‘short battery’). At self-identified sites with additional expertise, participants underwent a more extensive neuropsychological test battery that included the above tests and the Rey auditory verbal learning test trials I–VII, grooved pegboard with the nondominant hand, trail making parts A and B, finger tapping with the dominant hand, Rey auditory verbal learning test trial VIII 30-min delay, basic choice reaction time (CalCAP), and sequential reaction time (CalCAP) (‘long battery’). The short and the long batteries have been used routinely in studies of HIV-associated cognitive impairment [11,12].
The same procedures were repeated 24 and 52 weeks after beginning therapy. If participants discontinued their antiretroviral therapy or withdrew from the study for any reason more than 4 weeks after a previous evaluation, they repeated the evaluation. Participants who changed their regimen because of side effects continued in the study.
HIV RNA in centrifuged CSF and plasma was measured by the Amplicor HIV-1 Monitor test with ultrasensitive specimen preparation (Roche Molecular Systems, Pleasanton, California, USA). Samples with less than 50 copies/ml were considered to be undetectable. Suppression of HIV RNA was defined as a decline from detectable to undetectable. HIV RNA copies/ml were expressed as log10.
To estimate CNS penetration of a drug regimen, we used the CNS penetration effectiveness (CPE) rank, which assigns each antiretroviral agent a value of 0 (low penetration), 0.5 (intermediate penetration), or 1.0 (good penetration) . These ranks are summed to determine the CPE rank of a regimen. This method categorizes CNS drug penetration on the basis of virologic and pharmacologic data and has been recently validated . We constructed receiver operator characteristic curves to determine that the optimal cut-off point for CPE rank was at least 2. Ritonavir was not considered in the calculation of the CPE rank if it was used in low dose to increase drug levels of concomitantly administered protease inhibitors.
Z-scores were calculated for each neuropsychological test using age-adjusted norms, and a composite Z-score for the short battery (NPZ4) and the long battery (NPZ8) was calculated at each visit, with lower scores reflecting poorer performance and higher scores reflecting better performance. CD4 cell count estimates were based on a 50-cell increase.
Generalized estimating equations with an autoregressive correlation structure were used to examine associations between variables. The initial multivariate models included CPE, controlling for covariates with a P-value of less than 0.15 in the univariate models. A backward covariate selection strategy was applied until a P-value of less than 0.15 was reached for all covariates except CPE in the models. Results are expressed as 95% confidence intervals (CIs) = (lower confidence limit–upper confidence limit). P-values of 0.05 or less were considered statistically significant.
One hundred and one participants were enrolled in the study. Twenty-two participants were not included in the analysis (Fig. 1). Sixty participants were seen in all three study visits (Fig. 1). Participants who prematurely ended study participation before the 24- or 52-week visits did not differ significantly from those who completed the study with regard to demographic and laboratory features.
The characteristics of the 79 study participants included in the analyses are shown in Table 1. Eight participants were receiving antiretrovirals at study entry, before beginning their new regimens. In seven participants, this regimen was potent and, in one, it was not. Thirty-five participants had taken antiretrovirals in the past (‘experienced’), and 44 had never taken antiretrovirals (‘naive’). Participants who were antiretroviral naive had significantly higher peripheral blood CD4+ T cell count (median 127 vs. 106 cells/μl, P = 0.04) compared with antiretroviral-experienced participants but did not differ with respect to entry plasma or CSF HIV RNA concentration or neuropsychological function. In participants with detectable CSF HIV RNA at baseline, median [interquartile range (IQR)] baseline plasma HIV RNA was 4.88 (4.66–5.34) copies/ml.
Overall, participants took 48 different drug regimens after study entry. Regimens with a CPE rank less than 2 were prescribed at 57 (42%) of 135 visits. The median number of agents in a regimen was 3.0 (IQR = 3.0–4.0), and the median CPE was 2.0 (IQR = 1.5–2.5). Nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, defined as an NNRTI and at least two nucleoside reverse transcriptase inhibitors and no protease inhibitors, were taken at 53 (39%) visits. The median CPE rank in the NNRTI-based regimens and the remaining regimens was 2.0. On the basis of all visits, and adjusted for repeated measures, the number of antiretroviral agents in a regimen was greater when the CPE rank was higher (r = 0.47, P < 0.001) .
Suppression of cerebrospinal fluid HIV RNA
CSF HIV RNA was never detectable when plasma HIV RNA was undetectable. This relationship held both in experienced and naive participants (data not shown). CSF HIV RNA was rarely detectable when plasma HIV RNA was less than 1000 copies/ml (data not shown).
In the univariate analysis, the odds of suppression of CSF HIV RNA were higher in participants who were antiretroviral naive than in those who were antiretroviral experienced [odds ratio (OR) = 6.06, 95% CI = 1.54–23.77] (Table 2). Compared with those prescribed a regimen with a CPE rank of less than 2, there was a trend toward higher odds of suppression of CSF virus in participants who were prescribed a regimen with a CPE rank of at least 2 (OR = 3.22, 95% CI = 0.95–10.87). There was no significant relationship between suppression of CSF HIV RNA and the use of an NNRTI-containing regimen.
In multivariate models, the odds of suppression of CSF virus were higher in participants who were antiretroviral naive at study entry than in those who were antiretroviral experienced (OR = 4.86, 95% CI = 1.11–21.27, P = 0.04). Taking into account being naive and total number of antiretroviral agents, participants who were prescribed a regimen with a CPE rank of at least 2 had significantly higher odds of suppression of CSF virus (OR = 4.10, 95% CI = 1.06–15.91, P = 0.04). There was a trend toward lower odds of suppression of CSF virus in participants who were prescribed more antiretroviral agents (OR = 0.64, 95% CI = 0.40–1.01, P = 0.06).
Suppression of plasma HIV RNA
In the univariate analysis, the odds of suppression of plasma HIV RNA were higher in participants who were antiretroviral naive (OR = 3.87, 95% CI = 1.63–9.20, P = 0.002) and in those who were prescribed an NNRTI-based regimen (OR = 2.71, 95% CI = 1.13–6.47, P = 0.03). For every 50-cell increase in entry CD4 cell count, the odds of suppression of plasma HIV RNA were 1.24-fold (95% CI = 1.03–1.49, P = 0.02) higher. There were no significant associations between suppression of plasma HIV RNA and CPE rank of at least 2 or number of agents in a regimen.
Seventy-five participants underwent the four-test battery, and 52 participants underwent the eight-test battery (Table 1). On the basis of clinical convention and prior experience, a Z-score of −0.5 or less was chosen as the definition of cognitive impairment . Twenty-six participants were impaired on the basis of their entry NPZ4 score, and 17 participants were impaired on the basis of their entry NPZ8 score. We restricted analyses of the effect of entry characteristics on neurocognitive performance over the course of the study to those participants who were cognitively impaired at study entry. Data from 39 follow-up visits were available for analysis of NPZ4, and data from 26 follow-up visits were available for analysis of NPZ8. Participants who were included in these analyses differed from those who were not included. As expected, compared with participants not included in the NPZ4 analysis, participants included in the NPZ4 analysis had lower entry peripheral blood CD4+ T cell count (median 94 vs. 132 cells/μl, P = 0.05). They also had fewer years of education (median 12 vs. 14 years, P = 0.01) and were less likely to be white (23% vs. 62%, P = 0.002). Compared with participants not included in the NPZ8 analysis, participants included in the NPZ8 analysis had lower median peripheral blood CD4+ T cell count (54 vs. 126 cells/μl, P = 0.002) but did not differ in years of education or ethnicity.
There was no significant relationship between impaired NPZ4 at study entry and the CPE rank of the initial antiretroviral regimen. Specifically, 14 (54%) of 26 participants with impaired NPZ4 at entry were prescribed an initial antiretroviral regimen with a CPE rank of at least 2, and 12 (46%) were prescribed a regimen with a CPE rank of less than 2. Similarly, 25 (56%) of 45 participants with unimpaired NPZ4 at entry were prescribed an initial antiretroviral regimen with a CPE rank of at least 2, and 20 (44%) were prescribed a regimen with a CPE rank of less than 2.
Among the 26 participants with impaired NPZ4 at study entry, there was no significant difference in the baseline NPZ4 score in participants who were antiretroviral experienced compared with those who were antiretroviral naive [median (IQR) −1.10 (−1.19 to −0.67) Z-score vs. −1.09 (−1.89 to −0.84) Z-score]. Over the course of the study, there was no significant difference in the number of antiretrovirals prescribed in the ten antiretroviral-experienced compared with 16 antiretroviral-naive participants (data not shown).
Table 3 shows the results of univariate analyses of NPZ4 for participants with entry NPZ4 of −0.5 or less. For every 1 Z-score higher entry NPZ4, NPZ4 was 0.86 Z-score higher over the course of the study. Compared with participants who were prescribed an antiretroviral regimen with a CPE rank of less than 2, participants prescribed a regimen with a CPE rank of at least 2 had 1.08 Z-score lower NPZ4 over the course of the study. For every one agent added to a regimen, NPZ4 was subsequently 0.38 Z-score lower. There was no significant relationship between undetectable CSF HIV RNA at entry or the use of efavirenz and NPZ4 score. In multivariate models, the association with a CPE rank of at least 2 remained significant after controlling for entry NPZ4. Compared with participants who were prescribed an antiretroviral regimen with a CPE rank of less than 2, participants prescribed a regimen with a CPE rank of at least 2 had 0.66 Z-score (0.14–1.19, P = 0.01) lower NPZ4 over the course of the study.
Among those participants with entry NPZ4 of −0.5 or less, we examined the change in NPZ4 over the course of the study in those who were prescribed four agents vs. three and in those who were prescribed regimens with CPE rank of at least 2 compared with less than 2. There was a trend toward improvement in NPZ4 in participants who were prescribed three antiretrovirals [median (IQR) 0.36 (0.06–0.79) Z-score, P = 0.07], but NPZ4 did not change significantly in those prescribed four agents [median (IQR) −0.58 (−0.82 to −0.59) Z-score, P = 0.47]. NPZ4 improved significantly in participants who were prescribed a regimen with a CPE rank of less than 2 [median (IQR) 0.28 (0.19–0.87) Z-score, P = 0.02] but not in those prescribed regimens with CPE rank of at least 2 [median (IQR) 0.01 (−0.64 to 0.59) Z-score, P = 0.86].
In the univariate analysis of NPZ8 over the course of the study in participants with entry NPZ8 of −0.5 or less, the negative relationship between more antiretroviral agents in a regimen and neurocognitive performance remained highly significant, but the magnitude of the effect was small (Table 4). For every one agent added to a regimen, NPZ8 was 0.11 Z-score lower. CPE rank was not significantly related to NPZ8 over the course of the study. The small number of observations in this analysis precluded the construction of multivariate models.
The goal of this study was to determine whether patients who begin or change to an antiretroviral regimen with ‘good’ CNS penetration, defined as a CPE rank of at least 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 participants with cognitive impairment, and, as expected, we found that participants with neurocognitive impairment had lower median peripheral blood CD4+ T cell count.
We found that regimens with a CPE rank of at least 2 conveyed greater odds of suppression of CSF HIV RNA. The 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 .
We also found that participants who were antiretroviral naive had significantly higher odds of suppression of CSF virus than experienced participants, even after taking into account CPE rank or number of antiretrovirals in a regimen. A longitudinal study of 29 individuals who started or changed cART also found that being antiretroviral naive predicted greater decline in CSF HIV RNA .
In contrast to our hypothesis that participants who were prescribed antiretroviral regimens with good CNS penetration would have better neurocognitive performance, we found the opposite. In the univariate analysis of NPZ4, compared with the use of a regimen with a CPE rank of less than 2, the use of a regimen with a CPE rank of at least 2 was significantly associated with poorer neurocognitive performance in participants who were cognitively impaired at study entry. The magnitude of the effect was substantial. In the same analysis, the use of antiretroviral regimens that contained more drugs was also significantly associated with poorer neurocognitive performance, although the magnitude of the effect was smaller. In multivariate analyses, a CPE rank of at least 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 . Among participants who were neuropsychologically impaired at study entry, we saw a significant improvement in NPZ4 in those who were prescribed regimens with a CPE rank of less than 2 and a trend toward improvement in those prescribed three agents (instead of four). In contrast, we saw no significant change in performance in participants prescribed a regimen with a CPE rank of at least 2 or who were prescribed four 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 [15,16]. Although few studies have examined the change in neuropsychological function after starting or changing ART, cognitive improvement has been documented, even when the regimen would not be considered ‘potent’ [9,17,18].
Nonetheless, the observation that neurocognitive impairment may be associated with specific components of a cART regimen is not without a precedent. For example, a longitudinal study showed that patients whose antiretroviral regimens contained ritonavir with another protease inhibitor or a regimen that contained at least three CNS-penetrant drugs had poorer motor performance than patients who did not receive the protease inhibitor combination or who were prescribed regimens with less than three CNS-penetrant drugs . The authors suggested that complex drug interactions could contribute to CNS toxicity. A proton magnetic resonance spectroscopy study showed that patients who took didanosine or stavudine had decreased frontal white matter N-acetyl aspartate concentrations compared with HIV-uninfected controls . This difference was not seen in patients who took zidovudine and lamivudine compared with 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 antiretroviral agents in a regimen, and measures of CNS drug penetration. First, the findings could be spurious. We limited our analysis of neurocognitive performance to participants 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 participants 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 participants included in the neurocognitive analyses, we did not see a relationship between the number of antiretroviral 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 the number of drugs in a regimen and suppression of plasma HIV RNA argues against the possibility that participants who took more antiretrovirals did so because they had less well controlled HIV.
Participants 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 the use of efavirenz, which has known cognitive adverse effects. However, we found no significant relationship between the 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-mortem or post-mortem brain tissue. We were unable to include data from 22 of the 101 enrolled participants. However, to our knowledge, our study population is the largest of any longitudinal investigation of patients beginning or changing ART. Antiretroviral regimens were not randomly allocated and were chosen by the treating provider or by the coenrolling clinical trial. It is thus possible that participants 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 participants may have been more likely to be cognitively impaired and to have received more antiretroviral agents. However, we found that, among those participants with baseline NPZ4 of −0.5 or less, there was no significant difference in baseline NPZ4 score in experienced compared with antiretroviral-naive participants. Similarly, there was no significant difference in the number of antiretroviral agents prescribed to antiretroviral-experienced compared with antiretroviral-naive participants 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 patients 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 antiretroviral 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 unable 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 antiretroviral regimens on cognition is required.
Award Number AI38858 and U01AI068636 from the National Institute of Allergy and Infectious Diseases supported this research.
Participating personnel, sites and grant support: Mary Gould, RN, BA and Teresa Spitz, RN, CCRC, Washington University in St. Louis, grant #AI69495 and NS32228; Margot Perrin, RN and N. Jeanne Conley, RN, University of Washington, Seattle, grant #AI 69434; Joan Dragavon, University of Washington Center for AIDS Research grant #AI-27757, and AIDS Clinical Trials Group Virology Support Laboratory grant #AI-38858; Margia Vasquez, RN and Maura Laverty RN, New York University/NYC HHC at Bellevue, grant #AI -69532 and M01RR00096; Paula Potter, RN and Dee Dee Pacheco, University of California, San Diego, grant #AI69432; Diane Gochnour, RN, The Ohio State University, grant #AI69474; Patricia Walton RN BSN, Case Western Reserve University, grant #AI69501; Colin Hall, MD, Cheryl Marcus, Wendy Robertson, University of North Carolina, grant #AI50410, AI69423, and RR00046; Anne Weisbeck, RN, University of Rochester, grant #AI69511 and grant #5-MO1 RR00044; Kathryn Carter, PA-C, Johns Hopkins University, grant # AI-69465 and RR-00052; Karen T Tashima, MD and Helen B Sousa, The Miriam Hospital, grant # AI69472; Bruce Cohen, MD and Linda Reisberg, RN, Northwestern ACTU, grant #AI69471; Nancy Hanks, RN, University of Hawai'i at Mano'a and Cecilia M. Shikuma, MD, University of Hawai'i at Mano'a- University of Hawaii, grant # AI34853; Dennis Kolson MD, PhD and Keith Mickelberg, RN, University of Pennsylvania, grant # AI69467 and CFAR grant #5-P30-AI-045008-07; Jorge L. Santana, MD and Olga Mendez, MD, University of Puerto Rico, grant #AI 69415; Sharon Shriver, AACTG Operations Office, Rockville, Maryland; Linda Millar, Frontier Sciences and Research Technology Research Foundation, Amherst, New York.
Author contributions: Christina M. Marra designed the study, drafted and critically reviewed the manuscript, and enrolled participants. Yu Zhao analyzed data, drafted, and critically reviewed the manuscript. David B. Clifford designed the study, drafted and critically reviewed the manuscript, enrolled participants, and provided funding. Scott Letendre drafted and critically reviewed the manuscript and enrolled participants. Scott Evans analyzed data, drafted and critically reviewed the manuscript, and reported to Data Safety Monitoring Board. Katherine Henry, Ronald J. Ellis, and Benigno Rodriguez critically reviewed the manuscript and enrolled participants. Robert W. Coombs designed the study, drafted and critically reviewed the manuscript, and provided technical support. Giovanni Schifitto critically reviewed the manuscript and enrolled participants. Justin C. McArthur designed the study, critically reviewed the manuscript, and enrolled participants. Kevin Robertson designed the study, drafted and critically reviewed the manuscript, and enrolled participants.
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