Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research

<p>Abstract</p> <p>Background</p> <p>There is conflicting information as to whether antiretroviral drugs with better central nervous system (CNS) penetration (neuroHAART) assist in improving neurocognitive function and suppressing cerebrospinal fluid (CSF) HIV RNA. The current review aims to better synthesise existing literature by using an innovative two-phase review approach (qualitative and quantitative) to overcome methodological differences between studies.</p> <p>Methods</p> <p>Sixteen studies, all observational, were identified using a standard citation search. They fulfilled the following inclusion criteria: conducted in the HAART era; sample size > 10; treatment effect involved more than one antiretroviral and none had a retrospective design. The qualitative phase of review of these studies consisted of (i) a blind assessment rating studies on features such as sample size, statistical methods and definitions of neuroHAART, and (ii) a non-blind assessment of the sensitivity of the neuropsychological methods to HIV-associated neurocognitive disorder (HAND). During quantitative evaluation we assessed the statistical power of studies, which achieved a high rating in the qualitative analysis. The objective of the power analysis was to determine the studies ability to assess their proposed research aims.</p> <p>Results</p> <p>After studies with at least three limitations were excluded in the qualitative phase, six studies remained. All six found a positive effect of neuroHAART on neurocognitive function or CSF HIV suppression. Of these six studies, only two had statistical power of at least 80%.</p> <p>Conclusions</p> <p>Studies assessed as using more rigorous methods found that neuroHAART was effective in improving neurocognitive function and decreasing CSF viral load, but only two of those studies were adequately statistically powered. Because all of these studies were observational, they represent a less compelling evidence base than randomised control trials for assessing treatment effect. Therefore, large randomised trials are needed to determine the robustness of any neuroHAART effect. However, such trials must be longitudinal, include the full spectrum of HAND, ideally carefully control for co-morbidities, and be based on optimal neuropsychology methods.</p

Meaningful cognitive decline is uncommon in virally suppressed HIV, but sustained impairment, subtle decline and abnormal cognitive aging are not

Background: High antiretroviral therapy (ART) coverage and viral suppression among people with HIV (PWH) in Australia provide a unique context to study individual cognitive trajectories, cognitive aging and factors associated with longitudinal cognitive function during chronic and stable HIV disease. Methods: Participants from the Predictors of Adherence to Antiretroviral Therapy study (n = 457, recruited between September 2013 and November 2015, median age = 52 years, and all with HIV RNA 0.5). Meaningful cognitive change was statistically defined (decline or improvement versus stability, i.e., 90% CI, that is p < 0.05, 2-tailed) using a novel evidence-based change score: the linear mixed-effect regression (LMER)-based GZS change score. A separate LMER model with a top-down variable selection approach identified the independent effects of age and other demographic, HIV disease characteristics, socioeconomic and health-related factors on the demographically corrected GZS. The combined definitions of change and cross-sectional impairment enabled the identification of cognitive trajectories. Findings: At Month-12 and Month-24, 6% and 7% showed meaningful cognitive decline and 4% and 3% improved respectively. Only 1% showed sustained decline. Incident impairment due to subtle cognitive decline (i.e., below the threshold of meaningful cognitive decline) was 31% and 25% at Month-12 and Month-24, while 14% showed sustained impairment (i.e., cognitively impaired at all study visits). Older age (≥50 years) and time interaction was associated with lower demographically corrected GZS (β = −0.31, p < 0.001). Having a regular relationship, excellent English proficiency, and perceived stigma (avoidance) were associated with higher GZS (all p < 0.05). Relying on government subsidy, severe depression, and lower belief in ART necessity and higher concerns were associated with lower GZS (all p < 0.05). No HIV disease characteristics had a significant effect. Interpretations: Meaningful cognitive decline was not different from normal expectation in chronic stable HIV disease. Despite this, subtle cognitive decline, sustained cognitive impairment, and greater than normative-age cognitive aging were evident. Funding: Funding for the PAART study was provided in part by unrestricted educational grants from Gilead Sciences (www.gilead.com) (Grant Number: IN-AU-264- 0131), the Balnaves Foundation (www.balnavesfoundation.com), the Victorian Department of Health and Human Services (Australia) (www.dhs.vic.gov.au/home), Western Australia Health (www.health.wa.gov.au), the ACT Ministry of Health (Australia) (www.health.act.gov.au), and in-kind support from the Queensland Department of Health (Australia) (www.health.qld.gov.au), and NHMRC Partnership grant APP1058474 (PI: Carr, Andrew)

HIV-associated neurocognitive disorder in Australia: a case of a high-functioning and optimally treated cohort and implications for international neuroHIV research

Abstract The Australian HIV-infected (HIV+) population is largely comprised of high-functioning men who have sex with men (MSM). Like other English-speaking countries, Australia mostly relies on US neuropsychological normative standards to detect and determine the prevalence of neurological disorders. Whether the US neuropsychological (NP) normative standards are appropriate in Australian HIV+ MSM has not been established. Ninety virally suppressed HIV+ and 49 HIV-uninfected (HIV−) men (respectively 86 and 85 % self-reported MSM; mean age 54 and 56 years, mean premorbid verbal IQ estimate 110 and 111) undertook standard NP testing. The raw neuropsychological data were transformed using the following: (1) US standards as uncorrected scaled scores and demographically corrected T scores (US norms); and (2) z scores (without demographic corrections) derived from Australian comparison group scaled scores (local norms). To determine HIV-associated neurocognitive disorder prevalence, we used a standard definition of impairment based upon a battery-wide summary score: the global deficit score (GDS). Impairment classification (GDS≥0.5) based on the local norms was best at discriminating between the two groups (HIV− = 14.3 % vs. HIV+ = 53.3 %; p&lt;0.0001). This definition was significantly associated with age. Impairment classification based on the US norms yielded much lower impairment rate regardless of the HIV status (HIV−=4.1 % vs. HIV+=14.7 %; p= 0.05), but was associated with historical AIDS, and not age. Both types of summary scores were associated with reduced independence in activities of daily living (p≤ 0.03). Accurate neuropsychological classifications of high (or low) functioning individuals may need country-specific norms that correct for performancebased (e.g., reading) estimates of premorbid cognition in addition to the traditional demographic factors

APOE ε4 moderates abnormal CSF-abeta-42 levels, while neurocognitive impairment is associated with abnormal CSF tau levels in HIV+ individuals – a cross-sectional observational study

Background: Cerebrospinal fluid (CSF) biomarkers Aβ1-42, t-tau and p-tau have a characteristic pattern in Alzheimer’s Disease (AD). Their roles in HIV-associated neurocognitive disorder (HAND) remains unclear. Methods: Adults with chronic treated HIV disease were recruited (n = 43, aged 56.7 ± 7.9; 32% aged 60+; median HIV duration 20 years, \u3e95% plasma and CSF HIV RNA \u3c50 cp/mL, on cART for a median 24 months). All underwent standard neuropsychological testing (61% had HAND), APOE genotyping (30.9% carried APOE ε4 and 7.1% were ε4 homozygotes) and a lumbar puncture. Concentrations of Aβ1-42, t-tau and p-tau were assessed in the CSF using commercial ELISAs. Current neurocognitive status was defined using the continuous Global Deficit Score, which grades impairment in clinically relevant categories. History of HAND was recorded. Univariate correlations informed multivariate models, which were corrected for nadir CD4-T cell counts and HIV duration. Results: Carriage of APOE ε4 predicted markedly lower levels of CSF Aβ1-42 in univariate (r = -.50; p = .001) and multivariate analyses (R2 = .25; p \u3c .0003). Greater levels of neurocognitive impairment were associated with higher CSF levels of p-tau in univariate analyses (r = .32; p = .03) and multivariate analyses (R2 = .10; p = .03). AD risk prediction cut-offs incorporating all three CSF biomarkers suggested that 12.5% of participants had a high risk for AD. Having a CSF-AD like profile was more frequent in those with current (p = .05) and past HIV-associated dementia (p = .03). Conclusions: Similarly to larger studies, APOE ε4 genotype was not directly associated with HAND, but moderated CSF levels of Aβ1-42 in a minority of participants. In the majority of participants, increased CSF p-tau levels were associated with current neurocognitive impairment. Combined CSF biomarker risk for AD in the current HIV+ sample is more than 10 times greater than in the Australian population of the same age. Larger prospective studies are warranted

Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury

Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (1H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std β=-0.73; p=0.007) and posterior cingulate (Std β=-0.61; p=0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3+CD49d+integrin β7-, CCR5+CD4+ T-cells were highly enriched in CSF, compared with PBMC (p <0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4+ T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products

The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% – depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects — particularly apathy — as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study

White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration

The objective of the current study was to quantify the degree of white matter (WM) abnormalities in chronic and virally suppressed HIV-infected (HIV+) persons while carefully taking into account demographic and disease factors. Diffusion tensor imaging (DTI) was conducted in 40 HIV- and 82 HIV+ men with comparable demographics and life style factors. The HIV+ sample was clinically stable with successful viral control. Diffusion was measured across 32 non-colinear directions with a b-value of 1000 s/mm2; fractional anisotropy (FA) and mean diffusivity (MD) maps were quantified with Itrack IDL. Using the ENIGMA DTI protocol, FA and MD values were extracted for each participant and in 11 skeleton regions of interest (SROI) from standard labels in the JHU ICBM-81 atlas covering major striato-frontal and parietal tracks. We found no major differences in FA and MD values across the 11 SROI between study groups. Within the HIV+ sample, we found that a higher CNS penetrating antiretroviral treatment, higher current CD4+ T cell count, and immune recovery from the nadir CD4+ T cell count were associated with increased FA and decreased MD (p &lt; 0.05-0.006), while HIV duration, symptomatic, and asymptomatic cognitive impairment were associated with decreased FA and increased MD (p &lt; 0.01-0.004). Stability of HIV treatment and antiretroviral CNS penetration efficiency in addition to current and historical immune recovery were related to higher FA and lower MD (p = 0.04-p &lt; 0.01). In conclusion, WM DTI measures are near normal except for patients with neurocognitive impairment and longer HIV disease duration

Neurocognitive function in HIV infected patients on antiretroviral therapy

OBJECTIVE To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. DESIGN We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. MAIN OUTCOME MEASURE NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. RESULTS Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was -0.5 (-1.2/-0) overall, and -0.3 (-0.7/0.1) and -1.4 (-2/-0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted-ND (p = 0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). CONCLUSIONS In this large group of HIV-infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. TRIAL REGISTRY ClinicalTrials.gov, NCT01230580

No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts

OBJECTIVE: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with >500 CD4+ cells/μL. DESIGN: Randomized trial. METHODS: The START parent study randomized participants to commence immediate versus deferred ART until CD4+ <350 cells/μL. The START Neurology substudy used 8 neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models. RESULTS: 592 participants had a median age of 34 years; median baseline CD4+ count of 629 cells/μL; the mean follow-up was 3.4 years. ART was used for 94% and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI: -0.062 to 0.027, p = 0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (p < 0.001 for increase from baseline). CONCLUSIONS: We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4+ cell counts above 500 cells/μL

Subcortical brain atrophy persists even in HAART-regulated HIV disease

The purpose of this study was to determine the pattern and extent of caudate nucleus and putamen atrophy in HIV-infected men with well-controlled immune status and viral replication. 155 men underwent structural brain magnetic resonance imaging; 84 were HIV-infected and 71 were uninfected controls. MRI data were processed using the Fully Deformable Segmentation routine, producing volumes for the right and left caudate nucleus and putamen, and 3-D maps of spatial patterns of thickness. There was significant atrophy in the HIV-infected men in both the caudate and putamen, principally in the anterior regions. The volume of the basal ganglia was inversely associated with the time since first seropositivity, suggesting that either there is a chronic, subclinical process that continues in spite of therapy, or that the extent of the initial insult caused the extent of atrophy