Neurocognitive performance is compromised in approximately 30%–50% of chronically HIV-infected individuals despite treatment with virally suppressive antiretroviral therapy (ART).1,2 Cognitive dysfunction negatively impacts daily function, quality of life, and increases morbidity and mortality.3–5 At present, clinically approved therapies for HIV-associated cognitive impairment do not exist.6
The neuropathogenesis of HIV-associated cognitive impairment has not been completely defined, but it is generally hypothesized that transmigration of HIV-infected monocytes into the central nervous system (CNS) provides entry of HIV into the brain and establishes a neuroinflammatory process that disrupts brain integrity and function.7–12 Persistent immune activation, driven in part by activated monocytes, is believed to be a major component of HIV neuropathogenesis.13 Monocyte/macrophage mediators such as soluble (s)CD163, monocyte chemoattractant protein (MCP)-1, and interleukin-6, have been linked to reduced cognitive performance among individuals on ART.9–11,14–16 Combined, these myeloid features represent a potential target for the treatment of cognitive dysfunction among individuals on ART.
Maraviroc (MVC), a C-C chemokine receptor type 5 (CCR5) antagonist, is Food and Drug Administration (FDA)–approved as an antiretroviral medication to be used with other antiretroviral agents in CCR5-tropic HIV-infected individuals. MVC has been associated with improved cognitive performance and reduction of plasma markers of monocyte activation.17–19 In a previous single-arm, open-label, 24-week study of MVC intensification in ART-treated, chronically infected individuals, we demonstrated improved cognitive performance, reductions in HIV DNA levels in monocytes, and in sCD163 levels, a plasma marker of monocyte activation.17 These data provide a platform for targeting chemokine receptors (CKRs) to improve cognitive performance in HIV-infected individuals.
The MCP-1/CCR2 axis has also been associated with cognitive dysfunction. In ART-naive HIV-infected Thai individuals, lower numbers of circulating activated monocytes expressing CCR2 were linked to worse cognitive performance.20 Reduced numbers of CCR2-expressing monocytes in the periphery suggest preferential trafficking of these cells into the brain toward MCP-1, a potent inducer of monocyte migration,21–24 contributing to neuroinflammation and reduced cognitive function.9,21 Given the involvement of CCR2 and CCR5 in HIV-related cognitive dysfunction, pharmacotherapeutic strategies that target both CKRs may be more effective than inhibiting a single CKR.
Cenicriviroc (CVC) is an oral, dual CCR2 and CCR5 antagonist with nanomolar potency, and a long plasma half-life25–27 currently in phase 3 evaluation for treatment of liver fibrosis in adults with nonalcoholic steatohepatitis (NCT03028740). In the phase 2b CENTAUR study 652-2-203 (NCT0221747528), 1 year of CVC treatment led to twice as many participants achieving improvement in fibrosis and no worsening of steatohepatitis when compared with placebo.29 CVC has also demonstrated anti-inflammatory and anti-fibrotic activity in animal models of liver disease, which was largely attributed to decreased monocyte/macrophage infiltration into the liver after hepatocyte injury.30–32 In a phase 2b clinical trial (NCT01338883) in ART-naive, HIV-infected individuals, CVC decreased viremia and sCD14 levels (marker of monocyte/macrophage activation).33 In an ex vivo study, CVC decreased HIV entry into peripheral blood mononuclear cells (PBMCs).34 Considering the role of monocyte inflammation and migration into the CNS in the neuropathogenesis of HIV, we hypothesized that CCR2 and CCR5 blockade would improve cognitive function by decreasing monocyte activation and migration into the CNS.
The study was approved by the University of Hawaii Human Subjects Program, received clearance to proceed from the FDA [IND 119671], and was registered at ClinicalTrials.gov (NCT02128828). Twenty chronically infected aviremic (HIV RNA <50 copies/mL) individuals aged 18–70 years on uninterrupted ART for >1 year were enrolled into the single-arm, open-label, 24-week pilot study. Participants were required to be on the same ART regimen for at least 6 months before entry. Below-normal cognitive performance was defined as performance of <−0.5 SD below published normative standards in a cognitive domain or global cognitive performance (NPZ Global). Exclusion criteria included currently receiving or having used a CCR5 antagonist as part of an ART regimen within 6 months of entry, on-going need for use of medications known to have unacceptable drug–drug interactions with CVC (provided by the manufacturer of CVC), history of plasma HIV RNA >100 copies per milliliter within 6 months of screening, chronic hepatitis B or C or diagnosis of any other active or chronic liver disease, chronic uncontrolled seizures or significant past history of CNS disease or head trauma, depression (Beck Depression Inventory-II total score >29), chronic illnesses or cancers except for stable treated hypogonadism or hypothyroidism, unstable cardiovascular or cerebrovascular disease, or the following abnormal laboratory values: hemoglobin <8.5 g/dL, absolute neutrophil count <1000/μL, platelet count <100,000/μL, AST and ALT ≥2.5 upper limit of normal, lipase >2.0 × upper limit of normal, estimated creatinine clearance by the Cockcroft–Gault Equation ≤30 mL/min, and bradycardia (<50 beats/min).
All study visits were conducted at a single site at the University of Hawaii (UH) Clinics at Kaka'ako. After written informed consent and screening, CVC was administered once-daily with food in dosage adjusted for each participant's ART regimen and other medications as per the manufacturer's recommendations. Individuals with ART regimen consisting of a nucleoside reverse transcriptase inhibitor (NRTI) and unboosted/boosted atazanavir or boosted darunavir received 50 mg (1 tablet) of CVC, individuals taking dolutegravir- or raltegravir-based ART received 200 mg (4 tablets) of CVC, and individuals receiving efavirenz received 400 mg (8 tablets) daily. Research bloods were drawn at entry and at weeks 4, 8, 12, and 24.
Neuropsychological (NP) testing was conducted at entry and week 24 by trained psychometrists. Testing was conducted in a quiet room, and participants were provided breaks as needed throughout the testing sessions. The test battery (Table 1) was comprising measures known to be sensitive to HIV-related infection including attention (A); working memory (WM); psychomotor speed (PM); visuospatial reasoning (VPR); executive function (EF); learning and memory (LM), and gross motor (GM).35,36 Raw scores were converted into standardized z-scores according to demographically adjusted norms.37,38 Global cognitive function (Global NPZ) was defined by aggregating the domain-specific NPZ scores.
Assessments of Plasma-Derived Soluble Biomarkers
Plasma sCD163, sCD14 and neopterin were quantified at entry and weeks 8, 12, and 24 by single-analyte ELISA array (Trillium Diagnostics, Bangor, ME; R&D Systems, Minneapolis, MN and Thermo Scientific, Waltham, MA, respectively).
Quantification of Monocyte and T-Cell Subset Frequencies and CKR Expression
Monocyte and T cell subpopulations were measured at entry and week 24 after CVC by flow cytometry. Briefly, cryopreserved PBMCs were placed in 96-well polypropylene round bottom plates and stained with Live/Dead Fixable Red Dead Cell Stain (Invitrogen, Carlsbad, CA) for 15 minutes at room temperature followed by 2, 10-minute sequential incubations with conjugated monoclonal antibodies (mAbs) against CCR2 [AlexaFluor647, Catalog Number (Cat) 558406] and CCR5 [phycoerythrin (PE), Cat 555993] at 37°C.39 Cells were then stained at room temperature for 30 minutes with mAbs against CD3 [brilliant violet (BV) 711, Cat 317328], CD4 [(peridinin chlorophyll protein) PerCP-Cyanine (Cy)5.5, Cat 300530], CD8 (PE-Cy5, Cat 555368), CD14 (AlexaFluor700, Cat 557923), CD16 (BV421; Cat 343113), CD7 (PE-Cy7, Cat 343113), CD19 (PE-Cy7, Cat 557835), CD20 (PE-Cy7, Cat 560735), CD11b (AlexaFluor488, Cat 557701), and human leukocyte antigen-D related [allophycocyanin-H7, Cat 561358]. Cells were fixed with 1% PFA, and data were acquired on a custom 4-laser BD LSRFortessa (BD Bioscience, San Jose, CA). Compensation and gating analyses were performed using FlowJo (FlowJo LCC, Ashland, OR). All mAbs were purchased from BD Bioscience (San Jose, CA) except for Live/Dead Stain (Invitrogen), and CD3-BV711, CD4-PerCP-Cy5.5, and CD16-BV421 (BioLegend, San Diego, CA). The gating strategy for identification of CD4+ and CD8+ T cells, and monocyte subsets, along with CKR expression, is shown in Figure 1, Supplemental Digital Content, http://links.lww.com/QAI/B172. Median viability for the frozen PBMC samples was 93.8% (interquartile range 25th–75th: 89.7%–96.1%). Samples were excluded if the viability was below 80%.
Monocyte subset counts were calculated by multiplying monocyte number (Mono/μL) from the white blood cell count obtained from the clinical laboratory values and the percent frequency generated by flow cytometry. CD4+ and CD8+ T cell counts were obtained from the white blood cell count.
Descriptive statistics for all continuous and categorical variables are reported as median (interquartile range) and n (percent), respectively. Wilcoxon signed-rank test was used to assess changes from entry to week 24, and Spearman correlation was used to assess the relationship between continuous variables. The magnitude of change from entry to week 24 in NP testing was examined in relation to the SEM estimates where applicable based on previous studies.40 All statistical analyses were performed using SAS version 9.4 (Cary, NC: SAS Institute Inc, 2002–2012). A 2-sided P value <0.05 was regarded as statistically significant for all tests, whereas P values between 0.05 and 0.1 were reported as trends.
Study Participant Clinical and Demographic Characteristics
Seventeen of the 20 enrolled participants completed the study. One participant withdrew from the study because of grade 1 nausea, and 2 participants left the study for nonmedical personal issues. Baseline participant characteristics of the 17 participants who completed the study are found in Table 2. The participants were generally older, male except for one participant, with a long history of living with HIV and being on ART. Of the 17 participants, 6 were on dual NRTIs (all on tenofovir/emtricitabine) and protease inhibitor (PI) regimens using boosted atazanavir or boosted darunavir; 7 were on dual NRTIs (either tenofovir/emtricitabine or abacavir/lamivudine) and integrase inhibitor [integrase strand transfer inhibitor (INSTI)] therapy with either dolutegravir or raltegravir; and one was on a dual NRTI (tenofovir/emtricitabine) and a non-NRTI (NNRTI, efavirenz). The other 3 patients were on less common regimens consisting of a triple NRTI regimen (zidovudine, lamivudine, and abacavir); triple NRTI (tenofovir, emtricitabine, and abacavir) plus an NNRTI (efavirenz); and dual NRTI (tenofovir and emtricitabine) plus a protease inhibitor (darunavir) and an INSTI (raltegravir).
CVC Tolerance by Study Participants
A total of 58 clinical adverse events were observed in 14 participants (n = 49, grade 1 and n = 9, grade 2). Grade 2 clinical adverse events included loose stools (n = 2; 10%), nausea (n = 1; 5%), abdominal cramps (n = 1; 5%), and fatigue (n = 1; 5%). In addition, 17 laboratory adverse events were reported in 6 participants while on study drug (n = 13 grade 1; n = 2 grade 2 and n = 2 grade 3). The grade 2 adverse events included elevated lipase and creatinine. The grade 3 adverse events included asymptomatic elevated lipase at weeks 24 and 28, both of unclear relationship to CVC. Average/overall compliance was 95%. The lowest compliance recorded in a patient was 65% between weeks 4 and 8. At all other time points recorded, compliance was at least 80%.
Changes in Neuropsychological Performance After CVC Treatment
After 24 weeks, significant improvements were noted in Global NPZ, attention, and WM (Table 3 and Fig. 1). Trends toward improved psychomotor speed and visuospatial performance were also observed (Table 3 and Fig. 1). No significant changes were seen in executive function, learning and memory, or gross motor (Table 3 and Fig. 1).
In the attention domain, trends toward improvements in performance were observed on the CalCap Choice test [median increase = 0.57 (−0.45, 1.18), P = 0.071] and Digit Span Total [median increase = 0.33 (0, 0.66), P = 0.094; see Table 1, Supplemental Digital Content, http://links.lww.com/QAI/B172]. Within the working memory domain, the greatest change was evident on the Letter Number Sequencing test [median increase = 0.33 (0, 1.00); P = 0.030], with a less robust effect seen on Digit Span [median increase = 0.33 (0, 1.33); P = 0.065], and no significant change on CVLT-II trial B was noted Table 1, Supplemental Digital Content, http://links.lww.com/QAI/B172). Comparisons of change in performance relative to the SEM of each neuropsychological measure revealed that initiation of CVC was associated with improvements in performance that exceeded the SEM on the Letter Number Sequencing test.40
Changes in Monocyte/Macrophage Activation
After 24 weeks of CVC, significant declines in plasma sCD163, sCD14, and neopterin were observed (Table 3). The trajectories of individual and overall trends are shown in Figure 2.
Changes in Leukocyte Counts
After 24 weeks, significant declines in total monocyte and classical monocyte counts along with significant increases in CD4+ T-cell and CD8+ T-cell counts were observed (Table 3). No significant changes were noted with CD4+/CD8+ ratios or the intermediate and nonclassical monocyte subset counts (Table 3).
Changes in CCR2 and CCR5 Expression on Monocyte and T-Cell Populations
Monocytes are composed of 3 distinct phenotypic subsets based on CD14 and CD16 expression into classical, intermediate, and non-classical monocytes.41 Functionally, these are defined by having scavenging/phagocytic, inflammatory, and patrolling properties, respectively.42,43 After 24 weeks, we observed a trend toward increased CCR2 expression on classical monocytes (Table 3). No significant changes were observed in CCR2 expression on intermediate and non-classical monocytes or in CCR5 expression on any of the monocyte subsets (Table 3). A significant increase in CCR2 levels on CD4+ T cells and significant increases in CCR5 expression on CD4+ and CD8+ T cells were noted (Table 3).
Correlations at Entry Between Leukocyte Measurements, Soluble Markers of Monocyte/Macrophage Activation, and Neuropsychological Testing
At entry, higher CCR2 levels on non-classical monocytes correlated with better performance on tests of attention (rho = 0.637; P = 0.026). Higher CCR5 expression on classical monocytes correlated with greater classical monocyte counts (rho = 0.587; P = 0.045). I-n addition, sCD14 positively correlated with nonclassical monocyte counts (rho = 0.755; P = 0.005). Trends noted at entry included a positive correlation between CCR5 levels on non-classical monocytes and non-classical monocyte counts (rho = 0.559; P = 0.059) and negative correlations between CCR5 on CD4+ T cells and visuospatial performance (rho = −0.574; P = 0.065), and between sCD14 and psychomotor speed (rho = −0.458; P = 0.064). No correlations were noted between sCD163 and neopterin, and monocyte counts, CKR expression, or performances on neuropsychological measures.
Our study demonstrated improved neuropsychological testing performance and reduced monocyte activation after 24 weeks of CVC in 17 virally suppressed HIV-infected individuals on stable ART. These data potentially link changes in monocyte/macrophage activation induced by CVC to improve cognitive performance in HIV-infected participants on virally suppressive ART.
Although the effects of CVC on cognitive performance were relatively subtle, the improvements approximated 0.5 SD, which is commonly referenced as a clinically meaningful degree of change.44 working memory, one of the subdomains that improved with CVC, is a specific component of executive function that is sensitive to HIV.45 The working memory cognitive domain encompasses short-term storage and manipulation of a limited amount of information in real time46,47 and is essential for effective implementation of daily activities such as driving, problem solving, and complex decision-making.48
As a single-arm study design, the potential influence of practice effects on the cognitive outcomes merits consideration. Practice effects are common and are typically pronounced between the first and second exposures.49 The cohort recruited in this study had undergone cognitive testing through previous longitudinal studies, and therefore, the impact of practice from baseline to 24 weeks in this study is less clear. The magnitude of change in the working memory domain, particularly on the Letter Number Sequencing test, exceeded the SEM, suggesting that the magnitude of change in performance observed in this study is unlikely to be due to practice effects.49 However, larger studies with a demographically matched control group are needed to address the important issue of practice effects more completely.
Potential therapeutic interventions for HIV-associated cognitive difficulties are limited. Our study suggests that modulation of monocyte/macrophage activation should be considered as a potential therapeutic intervention option to improve cognitive performance. Both sCD163 and sCD14, which are shed after monocyte/macrophage activation,50–52 have been previously shown to be biomarkers of cognitive performance in HIV. In ART-treated individuals, plasma sCD163 levels are elevated among individuals with more severe cognitive deficits.14 Plasma sCD14 levels have also been shown to be higher in HIV-infected individuals with worse performance in attention and learning.53 Similarly, in the Women's Interagency HIV Study (WIHS), higher plasma sCD163 levels were associated with worse global cognitive performance and lower scores on tests of verbal learning, verbal memory, executive function, and psychomotor speed.15 Higher sCD14 levels were associated with worse verbal learning, verbal memory, executive function, and psychomotor speed.15 Neopterin, which is produced by monocytes after stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ),54 remains elevated in treated HIV.55–58 Although we did not observe significant correlations between sCD163, sCD14, or neopterin with cognition at baseline, the concomitant decrease in soluble markers of monocyte/macrophage activation with improved cognitive performance is suggestive of a direct link. Further studies are needed to explore the causal pathways that cannot be established in this preliminary study.
Decreases in monocyte counts in the periphery may be a result of diminished rates of egress of classical monocytes out of the bone marrow because murine studies have demonstrated that CCR2 is required for monocyte trafficking out of the bone marrow into the circulation.42,59 Increases in CKRs observed in our study are in concert with a double-blind, placebo-controlled randomized trial of MVC where CCR5+, CD4+, and CD8+ T cell frequencies were significantly increased in the MVC group compared with placebo.60 Although CKR levels on the monocyte subsets from the periphery were not significantly altered by CVC, we did note a limited number of correlations between CKR expression and cognitive performances, suggesting modulation of CKRs have beneficial effects. In fact, murine models have shown that decreased function of CCR5 lead to enhanced hippocampal-dependent learning and memory, whereas neuronal CCR5 overexpression caused memory deficits.61 Moreover, treatment of mice with HIV peptide decreases long-term potentiation deficits that can be prevented by CCR5 knockout or knockdown.61
Four of the 17 participants had worse global cognition after 24 weeks of CVC. There were no evident factors that contributed to the decline in cognitive performance in 3 of the 4 participants. One participant tested positive for methamphetamines, marijuana and amphetamines at week 24 but not at entry, which could have affected cognitive performance at the follow-up visit. Removal of this case did not affect the pattern of results. When comparing the participants who exhibited worse cognition after 24 weeks of CVC to the remainder of the sample revealed no significant differences in clinical or laboratory parameters, including monocyte activation, leukocyte counts, age, or years infected (data not shown).
This study was planned as a small exploratory study. The conclusions of this study are limited by the small sample size of only 17 evaluable participants. In addition, the design was that of a single-arm study without a placebo control arm that limits our ability to conclusively define a causal link between CVC and changes in cognition and monocyte/macrophage immune activation. Finally, it should be noted that participants enrolled in this study were chronically infected with a long history of ART and we cannot make any conclusions on the potential effect of CVC on individuals who are ART-naive, or were treated early or in acute HIV infection. It is possible that CVC therapy may not have as great a response in early HIV when monocyte/macrophage inflammation is likely less than in those with delayed therapy, but it is equally possible that early intervention with CVC soon after diagnosis in conjunction with potent ART may prevent or diminish the occurrence of even mild forms of cognitive impairment.
The results of this small single-arm study are however intriguing. Given the lack of pharmacological interventions to improve cognition in HIV-infected individuals, further study of CVC in a randomized controlled study with a placebo arm and a longer follow-up period would be important to both confirm our findings and also to determine the magnitude and relevance of outcomes to patient care. Additional points of interest include characterizing monocyte/macrophages from tissues. The observed increases in CD4+ counts may indicate a restoration of the immune system and further study of the effect of CVC on T cells should be pursued. Finally, the unexpected increase in CD8+ counts also merits further investigation.
The authors thank the Hawaii Center for AIDS (HICFA) study participants and the HICFA clinical team.
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