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Association of antiretroviral therapy with brain aging changes among HIV-infected adults
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Download the PDF here
Download the PDF here
Download the PDF here
from Jules: ART neurotoxicity is a field that has received a little attention as reflected by this recent publication but not a lot of attention. It appears to me that all HIV+ after they age into their 50s and more so into their 60s are at risk for neurologic & cognitive impairment. So what is the contribution by ART regimens. This study looks at protease inhibitors and NNERTis but although it includes raltegravir the authors say their ability to examine integrase affects is limited due to not having enough data. I would ask regarding the use of already dead people's brains, if we could expect this to reflect those still living with HIV: We assembled 187 PLWH autopsy cases that were using ART drugs at the last clinical assessment in the National NeuroAIDS Tissue Consortium (NNTC, R432 and R458). Nonetheless, the future impact of ARTs on older aging's brin & cognitive function is an important question NOT receiving adequate attention, this is an example of the types of research we need more of related to aging research, that just gets too little research attention & these aging issues get too little discussion by ALL. Aging HIV+ over 65 are increasing experiencing cognitive & neurologic impairment MORE than age comparable HIV-negatives. This has a serious affect on functioning that for some has already caused functional decline and inability to perform normal functioning daily normal activities like shopping for food, keeping their home up, managing & navigating the healthcare system & their personal health. This combined with limited health literacy & increasingly less mobility & declining cognitive function is a recipe for serious problems, INCLUDING after these folks are unable to take care of themselves independently where will they be placed, institutionalized care will be required or will they even be considered, we are not ralking about this. Increasingly becoming homebound is emerging, there is no place for most of these individuals in institutionalized care, something we are NOT talking about.
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Association of antiretroviral therapy with brain aging changes among HIV-infected adults
Soontornniyomkij, Virawudha,b; Umlauf, Anyaa; Soontornniyomkij, Benchawannab; Gouaux, Bena; Ellis, Ronald J.a,c; Levine, Andrew J.d; Moore, David J.a,b; Letendre, Scott L.a,e
AIDS: Sept 10 2018
Objective: Antiretroviral therapy (ART) is currently recommended for all persons living with HIV (PLWH), regardless of their CD4+ T-cell count, and should be continued throughout life. Nonetheless, vigilance of the safety of ART, including its neurotoxicity, must continue. We hypothesized that use of certain ART drugs might be associated with aging-related cerebral degenerative changes among PLWH.
Design: Clinicopathological study of PLWH who were using ART drugs at the last clinical assessment.
Methods: Using multivariable logistic regression, we tested associations between use of each specific ART drug (with reference to use of other ART drugs) and cerebral degenerative changes including neuronal phospho-tau lesions, β-amyloid plaque deposition, microgliosis, and astrogliosis in the frontal cortex and putamen (immunohistochemistry), as well as cerebral small vessel disease (CSVD) in the forebrain white matter (standard histopathology), with relevant covariates being taken into account. The Bonferroni adjustment was applied.
Results: Darunavir use was associated with higher likelihood of neuronal phospho-tau lesions in the putamen [odds ratio (OR) 15.33, n = 93, P = 0.005]. Ritonavir use was associated with marked microgliosis in the putamen (OR 4.96, n = 101, P = 0.023). On the other hand, use of tenofovir disoproxil fumarate was associated with lower likelihood of β-amyloid plaque deposition in the frontal cortex (OR 0.13, n = 102, P = 0.012). There was a trend toward an association between emtricitabine use and CSVD (OR 13.64, n = 75, P = 0.099).
Conclusion: Our findings suggest that PLWH treated with darunavir and ritonavir may be at increased risk of aging-related cerebral degenerative changes.
Introduction
Early diagnosis of HIV infection followed by initiation of combination antiretroviral therapy (ART) has a clear clinical benefit in preventing the complications of HIV disease [1,2]. According to the United States Department of Health and Human Services (DHHS), guidelines for the use of ART drugs in adults and adolescents [3], ART is recommended for all persons living with HIV (PLWH), regardless of their CD4+ T-cell count. As currently available ART regimens do not cure HIV infection [4], ART should be continued throughout life [3], and therefore, understanding the long-term consequences of ART is critically important. Certain ART drugs may cause chronic toxicity to parenchymal and vascular components of the central nervous system (CNS), contributing to neurobehavioral symptoms [5-16]. Although ART drugs are used in combination, individual ART drugs are associated with distinct adverse events. For instance, efavirenz use can cause acute and chronic CNS adverse effects [12,13,17] even though it is commonly used in combination with tenofovir and emtricitabine. Many ART drugs, even within the same class, appear to differ in their toxicity profile [16].
Experimental studies on ART drug toxicity have been conducted in cell cultures and animal models. Several cell types were used in cell-culture experiments [15], such as neuronal cells [7,18-21], astroglia [22], oligodendroglia [23], endothelial cells [24-37], and vascular smooth muscle cells [35,38]. Brown et al. [19] reported that efavirenz induced β-secretase-1 protein expression and promoted soluble β-amyloid production in murine N2a neuronal cells [transfected with the Swedish mutant form of human β-amyloid precursor protein (APP) gene] and in Tg2576 mice expressing Swedish mutated APP. Efavirenz exposure also reduced primary mouse microglial phagocytosis of β-amyloid peptide [19].
These experimental studies provide important insights into potential ART neurotoxicity. However, there have been limited clinicopathological studies using postmortem brain samples to explore associations between ART and neuropathologic changes [23,39-41]. Regarding aging-related cerebral degenerative changes [42], Anthony et al. [41]reported an increase in hippocampal phospho-tau lesions (using AT8 antibody) in ART-treated PLWH compared with age-matched non-HIV participants. The same group [39] also observed markedly increased CD68-immunoreactive microglial activation in the hippocampus and basal ganglia in the absence of other significant neuropathologic changes in ART-treated PLWH compared with non-HIV participants. β-Amyloid plaque deposition, another aging-related cerebral degenerative change [42], was described in the cerebral neocortex [43-50] and hippocampal formation [41,51] of PLWH in autopsy studies. However, the association between ART and β-amyloid plaque deposition has not been studied systematically.
The potential effects of ART on cerebral small vessel disease (CSVD), commonly associated with aging, hypertension, and diabetes mellitus [52], have been explored in few autopsy studies [14,53]. A clinicopathological study of PLWH by our group [14] revealed an association between protease inhibitor-based ART and a higher risk of CSVD after statistically adjusting for diabetes mellitus. Similarly, an autopsy study by Morgello et al. [53] showed that protease inhibitor-based ART was associated with more severe CSVD compared with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART.
Taken together, aging-related cerebral degenerative changes have been observed in the postmortem brains of PLWH. Nonetheless, the occurrence of these changes in relation to specific ART drugs has not been strongly examined. In the present clinicopathological study, we aimed to analyze associations between specific ART drug use and aging-related cerebral parenchymal and vascular degenerative changes, including neuronal phospho-tau lesions, β-amyloid plaque deposition, microgliosis, astrogliosis, and CSVD [42,52]. Our study focused on ART drugs included in recommended initial regimens in the DHHS guidelines [3]. We chose to examine parenchymal degenerative changes in the middle frontal gyrus and putamen because changes in brain metabolite levels in these brain regions on magnetic resonance spectroscopy were shown to correlate with cognitive impairment in PLWH [54,55]. We hypothesized that use of certain ART drugs might be associated with aging-related cerebral degenerative changes among PLWH.
Discussion
We tested associations between specific ART drug use and nine neuropathologic changes denoting aging-related cerebral parenchymal and vascular degeneration in the brains of PLWH. We found that darunavir use was associated with neuronal phospho-tau lesions in the putamen. Ritonavir use was associated with marked Iba1 microgliosis in the putamen. On the other hand, tenofovir DF use was associated with a lower likelihood of β-amyloid plaque deposition in the frontal cortex. A trend toward an association between emtricitabine use and CSVD in the forebrain white matter was also observed.
The finding of an association between darunavir use and neuronal phospho-tau lesions in the putamen was based on the multivariable regression analysis of the relatively small number of darunavir users (eight cases, 8.6% of 93 cases). Hence, larger studies are warranted to confirm our finding. Also, there might be a sampling bias related to the possibility that PLWH received a darunavir/ritonavir (with the CPE rank of 3) [56] prescription because they had increased neurobehavioral symptoms.
Previous reports by Anthony et al. [39,41] showed that ART history was associated with neuronal phospho-tau lesions and microglial activation in postmortem brain samples. However, data on the use of individual ART drugs were not available in these two reports. CNS adverse events associated with ritonavir-boosted darunavir use were not common in clinical trials and postmarketing experience [63]. In cell-culture experiments using primary rat fetal brain neuronal cells, Robertson et al. [7] reported that 1-week exposure to darunavir or ritonavir led to a relatively lower risk of neuronal toxicity assessed by MAP2 immunoreactivity. Nonetheless, comparing the findings from various studies using different end points is not straightforward. Neuronal phospho-tau lesions, which progress from neuropil threads and pretangle neuronal soma to intracellular neurofibrillary tangles and extracellular (ghost) neurofibrillary tangles (indicative of neuronal loss), follow a chronic course that may be irreversible especially in later stages [60]. In the present study, 97% of 33 cases that showed neuronal phospho-tau lesions in the putamen had neuropil threads of grade-1 density (i.e. in the earliest stage). Neuronal phospho-tau lesions likely do not clinically manifest until they reach a critical threshold.
Among 77 cases with CSVD data, all 20 emtricitabine users had CSVD (see Table, Supplemental Digital Content 1, http://links.lww.com/QAD/B309). However, in the final multivariable analysis (19 emtricitabine users vs. 56 nonemtricitabine users), there was only a trend toward an association between emtricitabine use and CSVD after the Bonferroni correction (adjusted P = 0.099). The lack of non-CSVD cases among emtricitabine users is potentially an important finding, but it also makes the accurate estimation of OR computationally more challenging. Future studies with larger sample sizes are warranted to verify this finding. In our previous study [14], we focused on the protease inhibitor class of ART drugs and categorized ART regimens used (at the last clinical assessment) into protease inhibitor-based, nonprotease inhibitor-based, and no ART [i.e. use of (single-drug or dual-drug) non-ART regimens, discontinuation of ART, or being ART-naive). We found an association between protease inhibitor-based ART (with reference to no ART) and a higher risk of CSVD [14]. In the present study, however, we did not find any significant association between the use of any protease inhibitor drugs analyzed (i.e. atazanavir, darunavir, lopinavir, and ritonavir) and CSVD (with reference to the use of other ART drugs). The apparent discrepancy may be explained by a difference in the reference groups, in which ART-naive or ART-discontinuing cases were not included in the present study.
14 reference: We assembled 144 HIV-infected autopsy cases that had detailed data on antiretroviral medications and died during 1999-2011 in the CNTN. The University of California San Diego Human Research Protections Program approved the project and all study participants provided written informed consent to participate. The written consent to autopsy was also obtained. Pdf attached at top
We did not find any significant association between the CPE score and neuropathologic changes examined, which is not surprising. The CPE system has been designed to predict antiviral efficacy, not toxicity [9]. The CPE ranking does not take into account either CNS tissue drug concentrations or toxicity. In addition, the relationship between drug concentrations and toxicity can be completely different from that between drug concentrations and antiviral efficacy [11].
In the present study, associations between specific ART drug use and neuropathologic changes were observed in either the frontal cortex or putamen but not simultaneously. Variation in susceptibility to chronic ART toxicity may exist between different brain regions. During the human lifespan in general, the brain regional expansion of neuronal phospho-tau lesions and β-amyloid plaque deposition progresses with advancing age in characteristic sequences [42,64]. In addition, these neuropathologic changes can develop in association with the altered neural microenvironment in particular brain regions, for example, neuronal phospho-tau lesions in chronic traumatic encephalopathy [65].
The present study had limitations inherent to research using postmortem human samples. According to the current DHHS guidelines [3], ART drugs in the INSTI class (i.e. dolutegravir, elvitegravir, and raltegravir) are principal components of the recommended initial regimens. Nonetheless, INSTI-using cases have been relatively underrepresented in the NNTC cohort (personal communication with the NNTC Data Coordinating Center). Fewer PLWH are dying with INSTI-based ART, and therefore, fewer brains are available to research. This led to limited statistical power for testing associations between raltegravir (the only INSTI drug used in the present study) use and neuropathologic changes. As some ART drugs were always (e.g. darunavir and ritonavir) or often (e.g. emtricitabine and tenofovir DF) prescribed together, we cannot exclude the possibility that the effects of one ART drug resulted from the interaction effects of multiple ART drugs used simultaneously.
The duration of specific ART drug use might affect chronic neurotoxicity. Many PLWH change their ART regimen during their clinical course because of virologic failure or adverse events. In a given PLWH, the duration of specific ART drug use varied from one drug to another (data not shown). We selected cases based on the availability of complete data on the list of ART drugs currently used at the last clinical assessment. However, data on the duration of specific ART drug use were available in only a subset of these cases, and therefore could not be readily analyzed. We did not include brain HIV-1 RNA levels in the two brain regions examined as covariates because these data were available only in a small subset of cases. To compensate for this limitation, we included a histopathologic diagnosis of HIVE, which indicated productive HIV infection in the brain [57], and last-visit plasma HIV-1 RNA levels, as covariates.
In conclusion, our findings suggest that PLWH treated with darunavir and ritonavir may be at increased risk of particular aging-related cerebral degenerative changes including neuronal phospho-tau lesions and microgliosis. Larger autopsy cohorts of PLWH are needed to confirm an association between emtricitabine use and CSVD. Also justified are ART drug toxicity studies using multilayer cultures of vascular endothelial cells, smooth muscle cells, and pericytes, which mimic the in-vivo small vessel wall. The results of clinicopathological analyses can be used to guide experimental studies using animal models and cell systems to explore cause-effect relationships.
Results
The frequency distribution of neuropathologic outcomes within ART predictors and covariates is shown in Table, Supplemental Digital Content 1, http://links.lww.com/QAD/B309. The results of logistic regression models testing associations between biological covariates and neuropathologic outcomes, after adjusting for the two technical covariates, are shown in Table, Supplemental Digital Content 2, http://links.lww.com/QAD/B309. The results of final multivariable models testing associations between ART predictors and neuropathologic outcomes, after adjusting for applicable covariates, are shown in Table 2 and summarized in the following subsections.
Neuronal phospho-tau lesions
In the frontal cortex, neuronal phospho-tau lesions were present in 74 of 171 cases (43.3%). Of these 74 cases, 72 cases (97.3%) had neuropil threads of grade-1 density, another case with grade-2 density, and the remaining case with grade-3 density. In the putamen, neuronal phospho-tau lesions were present in 33 of 107 cases (30.8%). Of these 33 cases, 32 cases (97%) had neuropil threads of grade-1 density, and the remaining case had grade-2 density.
Darunavir use was associated with a higher likelihood of neuronal phospho-tau lesions in the putamen (OR 15.33; 95% CI 3.03-153.85; n = 93, adjusted P = 0.005; Table 2 ). In this analysis model, there were eight darunavir users (8.6%). Darunavir was used in combination with other ART drugs, such as ritonavir (eight cases, 100%), tenofovir DF (seven cases, 87.5%), and emtricitabine (six cases, 75%). Of 85 nondarunavir users, 40 (47.1%) used ritonavir, 45 (52.9%) used tenofovir DF, and 24 (28.2%) used emtricitabine. In the frontal cortex, none of the ART predictors was significantly associated with neuronal phospho-tau lesions (Table 2).
β-Amyloid plaque deposition
Almost all β-amyloid plaques found in the present study were of diffuse type [60]. In the frontal cortex, β-amyloid plaque deposition was present in 48 (focal in 33 and widespread in 15) of 171 cases (28.1%). In the putamen, β-amyloid plaque deposition was present in 17 (focal in 16 and widespread in 1) of 119 cases (14.3%).
Tenofovir DF use was associated with a lower likelihood of frontal β-amyloid plaque deposition (OR 0.13; 95% CI 0.03-0.48; n = 102, adjusted P = 0.012; Table 2 ). In this analysis model, there were 54 tenofovir DF users (52.9%), 34 of whom (63%) also used emtricitabine. Of 48 nontenofovir DF users, 3 (6.3%) used emtricitabine. Ritonavir use appeared to show a similar association (OR 0.30; 95% CI 0.10-0.85; n = 102), but this association did not survive the Bonferroni correction (adjusted P = 0.207). Note that APOE ε4 carrier status appeared to be associated with frontal β-amyloid plaque deposition in the final multivariable models (P < 0.020, data not shown), as did older age (P < 0.048, data not shown). In the putamen, none of the ART predictors was significantly associated with β-amyloid plaque deposition (Table 2 ).
Ionized calcium-binding adapter molecule-1 microgliosis
Ritonavir use was associated with marked Iba1 microgliosis in the putamen (OR 4.96; 95% CI 1.71-16.31; n = 101, adjusted P = 0.023; Table 2 ). In this analysis model, there were 51 ritonavir users (50.5%), 27 of whom (52.9%) also used lopinavir, 13 (25.5%) also used atazanavir, and 8 (15.7%) also used darunavir. Of 50 nonritonavir users, 5 (10%) used atazanavir and none used lopinavir or darunavir. Lopinavir use appeared to show a similar association (OR 4.44; 95% CI 1.36-17.39; n = 101), but this association did not survive the Bonferroni correction (adjusted P = 0.113). The APOE ε4 carrier status was associated with marked Iba1 microgliosis in the putamen in the final multivariable models (P < 0.0005, all models, data not shown). In the frontal cortex, the apparent association between abacavir use and marked Iba1 microgliosis (OR 3.09; 95% CI 1.06-10.03, n = 99; Table 2 ) did not remain significant after the Bonferroni correction (adjusted P = 0.353).
Glial fibrillary acidic protein astrogliosis
In either the frontal cortex or putamen, none of the ART predictors was significantly associated with marked GFAP astrogliosis (Table 2 ). The APOE ε4 carrier status appeared to be associated with marked GFAP astrogliosis in the putamen in the final multivariable models (0.021 < P < 0.029, data not shown).
Cerebral small vessel disease
In a subset of 77 cases from California NeuroAIDS Tissue Network where CSVD was evaluated, CSVD (of any degrees of severity) was diagnosed in 62 cases (80.5%). The two technical covariates were not included in analyses. There was a trend toward an association between emtricitabine use and CSVD (OR 13.64; 95% CI 1.61-1782.91; n = 75; Table 2 ; adjusted P = 0.099). In this analysis model, there were 19 emtricitabine users (25.3%), 17 of whom (89.5%) also used tenofovir DF. Of 56 nonemtricitabine users, 21 (37.5%) used tenofovir DF.
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