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High CNS Penetration Increased HIV Dementia
  We estimated that the incidence of HIV dementia increases by more than 70% after initiating an antiretroviral regimen with a high CPE score compared with a low score.
Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions
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Neurology 2014
Ellen C. Caniglia, Lauren E. Cain, Amy Justice, Janet Tate, Roger Logan, Caroline Sabin, Alan Winston, Ard van Sighem, Jose M. Miro, Daniel Podzamczer, Ashley Olson, Jose Ramon Arribas, Santiago Moreno, Laurence Meyer, Jorge del Romero, François Dabis, Heiner C. Bucher, Gilles Wandeler, Georgia Vourli, Athanasios Skoutelis, Emilie Lanoy, Jacques Gasnault, Dominique Costagliola, Miguel A. Hernán, On behalf of the HIV-CAUSAL Collaboration
The link between CNS penetration of antiretrovirals and AIDS-defining neurologic disorders remains largely unknown.
Methods: HIV-infected, antiretroviral therapy-naive individuals in the HIV-CAUSAL Collaboration who started an antiretroviral regimen were classified according to the CNS Penetration Effectiveness (CPE) score of their initial regimen into low (<8), medium (8-9), or high (>9) CPE score. We estimated "intention-to-treat" hazard ratios of 4 neuroAIDS conditions for baseline regimens with high and medium CPE scores compared with regimens with a low score. We used inverse probability weighting to adjust for potential bias due to infrequent follow-up.
Results: A total of 61,938 individuals were followed for a median (interquartile range) of 37 (18, 70) months. During follow-up, there were 235 cases of HIV dementia, 169 cases of toxoplasmosis, 128 cases of cryptococcal meningitis, and 141 cases of progressive multifocal leukoencephalopathy. The hazard ratio (95% confidence interval) for initiating a combined antiretroviral therapy regimen with a high vs low CPE score was 1.74 (1.15, 2.65) for HIV dementia, 0.90 (0.50, 1.62) for toxoplasmosis, 1.13 (0.61, 2.11) for cryptococcal meningitis, and 1.32 (0.71, 2.47) for progressive multifocal leukoencephalopathy. The respective hazard ratios (95% confidence intervals) for a medium vs low CPE score were 1.01 (0.73, 1.39), 0.80 (0.56, 1.15), 1.08 (0.73, 1.62), and 1.08 (0.73, 1.58).
Conclusions: We estimated that initiation of a combined antiretroviral therapy regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions.
We estimated that the incidence of HIV dementia increases by more than 70% after initiating an antiretroviral regimen with a high CPE score compared with a low score. However, we found little change in the incidence of toxoplasmosis, cryptococcal meningitis, and progressive multifocal leukoencephalopathy. These results are unexpected, and the interpretation of our effect estimates needs to be tempered by the limitations of our study.
In the only published study that has considered CPE scores in relation to neuroAIDS among HIV-positive individuals, the incidence of neuroAIDS was similar for a baseline CPE score of 10 or greater and for a baseline CPE score of 4 or less, but the small number of events resulted in a wide 95% CI (hazard ratio: 0.95; 95% CI: 0.53, 1.72). Furthermore, the study was not restricted to antiretroviral therapy-naive individuals and effect estimates for individual neuroAIDS conditions such as HIV dementia were not provided.24 Other studies of the association between CPE scores and risk of cognitive impairment (but not neuroAIDS) have had conflicting results.17,19,-,21,33
Our findings that CPE score does not affect the incidence of opportunistic infections may not be particularly surprising, because the development of these neuroAIDS conditions may be very closely connected to the degree of impaired cell-mediated immunity and not associated with antiretroviral penetration.4,5 In contrast, antiretroviral penetration into the brain may lead to deposition of β-amyloid plaques, which has been proposed as a possible explanation for a harmful effect of high CPE score on HIV dementia.34 One study observed a higher percentage of extracellular β-amyloid in cART-treated patients than in untreated HIV-positive individuals,35 and HIV-positive individuals with HIV-associated dementia have higher levels of intraneuronal β-amyloid immunoreactivity compared with HIV-positive individuals without HIV-associated dementia.34,-,36 However, the underlying mechanism through which antiretroviral penetration could cause HIV dementia remains unknown. The hypothesis that antiretroviral penetration increases the incidence of HIV dementia via deposition of β-amyloid plaques requires further research to determine whether these associations are in fact causal. Alternative pathways including antiretroviral-related direct neuronal damage and mitochondrial toxicity should also be evaluated.15
Another explanation for the higher dementia risk for regimens with a high CPE score is that these regimens are less effective to treat HIV disease, for example, because of incomplete adherence: 68% of individuals in the study deviated from their initial regimen at some point. However, both the high average proportion of follow-up spent on the initial regimen (58%) and the lack of a strong association between CPE score and opportunistic infections do not support this explanation.
Similar to any other observational study, the validity of our estimates relies on the untestable assumption that the measured covariates were sufficient to adjust for confounding and selection bias. It is possible that consideration of CPE scores is a factor for decisions concerning antiretroviral regimens in patients with neurocognitive symptoms. If individuals with neurocognitive symptoms are more likely to initiate antiretroviral regimens with higher CPE scores, the estimated effect on dementia might be explained by this confounding by indication. If this were the case, we would expect the estimated effect on dementia to disappear or to attenuate after a certain amount of time. However, excluding cases of HIV dementia occurring in the first year of follow-up does not materially change the results. Furthermore, restricting the analysis to individuals who initiated therapy before the introduction of the first CPE scoring system in 2008 does not affect the results.
Some limitations of our study should be noted. First, with relatively few events, the 95% CIs around our effect estimates are wide. However, our study is the largest one to date on this topic. Second, the cohorts included in this analysis are from developed countries; our results may not be generalizable to resource-limited settings or to other health care systems. Third, with the exception of VACS, the contributing cohorts used diagnostic procedures that reflect standard clinical practice in Europe. Excluding VACS from the analysis, however, did not significantly alter the results. Fourth, while our effect estimates are adjusted for cohort, we were not able to adjust for the individual centers within each cohort. Thus, some residual confounding due to centers within each cohort is theoretically possible. Finally, the average duration of follow-up in our study was approximately 3 years. Future studies will be needed to investigate the effect of antiretroviral penetration on the long-term incidence of neuroAIDS, as well as the effect of newer antiretrovirals that are not well represented in current studies, including ours.
We estimated that initiation of a cART regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions. These findings should be interpreted cautiously, and additional studies are needed to examine the effect of CPE score on the incidence of HIV dementia more closely. Together with additional data on the safety and effectiveness of different cART regimens, these results may be useful to plan the management of individuals with HIV infection.

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