A Phase I, Randomized, Controlled Clinical Study of CC-11050 in People Living With HIV With Suppressed Plasma Viremia on Antiretroviral Therapy (APHRODITE)

Afroditi Boulougoura; Erin Gabriel; Elizabeth Laidlaw; Vikram Khetani; Ken Arakawa; Jeanette Higgins; Adam Rupert; Robert J Gorelick; Keith Lumbard; Alice Pau; April Poole; Angela Kibiy; Princy Kumar; Irini Sereti

doi:10.1093/ofid/ofz246

. 2019 Jun 3;6(6):ofz246. doi: 10.1093/ofid/ofz246

A Phase I, Randomized, Controlled Clinical Study of CC-11050 in People Living With HIV With Suppressed Plasma Viremia on Antiretroviral Therapy (APHRODITE)

Afroditi Boulougoura ^1,², Erin Gabriel ³, Elizabeth Laidlaw ¹, Vikram Khetani ⁴, Ken Arakawa ⁴, Jeanette Higgins ⁵, Adam Rupert ⁵, Robert J Gorelick ⁵, Keith Lumbard ⁶, Alice Pau ¹, April Poole ¹, Angela Kibiy ¹, Princy Kumar ⁷, Irini Sereti ^1,^✉

PMCID: PMC6559277 PMID: 31211164

Abstract

Objective

Phosphodiesterase 4 inhibitors (PDE4i) are novel anti-inflammatory medications that have been approved for rheumatologic diseases and have been tested as host-directed therapy in tuberculosis. We examined the safety of CC-11050, a potent PDE4i in people living with HIV (PLWH) with suppressed HIV plasma viremia. We hypothesized that CC-11050 could be used to modulate HIV-related inflammation.

Method

Thirty PLWH on antiretroviral therapy (ART) ≥ 1 year with suppressed HIV viremia were enrolled and randomized 2:1 to 12 weeks of CC-11050 200mg twice daily or placebo with follow-up at weeks 2, 4, 8, 12, and 16. Primary endpoint was safety. Secondary endpoints were the effect of CC-11050 on cytokines, monocyte, and T-cell activation and potential pharmacokinetic interaction between CC-11050 and Efavirenz (EFV).

Results

At baseline, median age was 49.5 years and CD4 count 459 cells/µL. Most frequent adverse events (grade 1 and 2 only) in CC-11050 group were headache, diarrhea, nausea, cough, nasal congestion, and restlessness. Over a 12-week period, the CC-11050 group had lower level of IL-8, adjusted for baseline level, group, and week (0.72-fold, P = .02), lower percentage of NK cells (0.87-fold, P = .02) and higher IL-6 level (1.48-fold, P = .03) compared to placebo (0.87-fold, P = .02). CC-11050 and EFV co-administration did not reveal any pharmacokinetic interaction.

Conclusions

CC-11050 was well tolerated in PLWH, without affecting CD4 counts or plasma viremia, and led to a decrease in NK cells and plasma IL-8 level after 12-weeks of administration. Further study will be needed to elucidate the efficacy of CC-11050 as potential anti-inflammatory adjuvant strategy in HIV.

Keywords: HIV, inflammation, Phosphodiesterase 4 inhibitors (PDE4i), plasma biomarkers

In a phase 1, randomized, placebo-controlled, double-blinded clinical trial, CC-11050, a potent phosphodiesterase 4 inhibitor, was tested in people living with HIV who had suppressed plasma viremia on antiretroviral therapy. The drug was safe and well tolerated without affecting CD4 counts or viremia and with some evidence of biologic activity including decreases of NK cells and plasma IL-8 levels.

Introduction

Inflammation is an important contributor to HIV pathogenesis both prior to and after antiretroviral therapy (ART) initiation [1]. Inflammatory responses can occur abruptly soon after ART initiation, and are known as Immune Reconstitution Inflammatory Syndrome (IRIS), or they can be more chronic in nature in persons treated with ART with suppressed plasma HIV viremia and contribute to excess risk of non-AIDS–related serious events, such as cardiovascular or thromboembolic disease and liver or kidney diseases [2–5]. In addition, inflammation and immune activation have been associated with higher levels of HIV reservoirs, highlighting a potential role of inflammation in viral persistence [6–8].

Phosphodiesterase 4 inhibitors (PDE4i) is a group of novel anti-inflammatory medications that are involved in the regulation of pro-inflammatory mediators by blocking the degradation of cyclic adenosine monophosphate (cAMP) via inhibition of the PDE4 enzyme, resulting in an increase in cAMP in PDE4-expressing cells [9, 10]. Apremilast and roflumilast are FDA-approved PDE4i for the treatment of psoriasis or psoriatic arthritis and chronic obstructive pulmonary disease, respectively, while crisaborole is a topical medication approved for the treatment of mild-to-moderate atopic dermatitis [11–15]. PDE4i also have been tested as adjunctive therapies with anti-TB (tuberculosis) antibiotics in different animal models [16–18]. More specifically, in mouse and rabbit pulmonary tuberculosis models, CC-11050—a new potent PDE4i with better tolerability—has been shown to significantly improve disease severity, bacillary clearance, and pathology when administered as an adjunctive host-directed therapy with the antibiotic isoniazid [16]. An international phase II clinical study, to examine the safety and preliminary efficacy of CC-11050 as adjunctive host directed TB therapy (TB HDT) and assess its potential to shorten TB treatment or prevent permanent lung damage, is also currently under way (ClinicalTrials.gov identifier: NCT02968927).

We hypothesized that CC-11050 could be used as an anti-inflammatory drug in people living with HIV (PLWH) with the potential use to prevent or treat acute inflammation (eg, IRIS) or to suppress chronic residual immune activation. So far, CC-11050 was shown to decrease levels of multiple pro-inflammatory cytokines and chemokines and has been used as TB HDT in animal models. In addition, in contrast to other anticytokine therapies, CC-11050 is administered in oral formulations that would make it an attractive potential therapeutic agent for HIV. Because PDE4i drugs have not been tested in combination with ART in PLWH, a safety study would be imperative prior to designing efficacy studies. In this phase I, placebo-controlled, double-blinded study, we primarily examined the safety of CC-11050 in PLWH with suppressed plasma HIV viremia.

METHODS

Study Design

APHRODITE was a randomized, placebo-controlled, double-blinded, 12-week, comparative, phase I clinical study to assess the safety of CC-11050, administered to PLWH receiving ART with suppressed plasma viremia (ClinicalTrials.gov identifier: NCT02652546). The study was approved by the National Institute of Allergy and Infectious Diseases, and written informed consent was obtained from all participants prior to any study procedures.

The study was performed under an Investigational New Drug and was monitored by an independent data and safety monitoring board (DSMB). Eligible participants were 18 years or older, HIV+ persons who had received ≥ year of ART, and had been on a stable regimen for ≥ 3 months prior to screening. Protease inhibitor-based ART regimen or regimen that included cobicistat were excluded. Participants had plasma HIV-1 RNA <50 copies/mL at screening and a body mass index 18.5 < (body mass index) ≤ 35 kg/m2.

Exclusion criteria were pregnancy, contra-indicated medications due to interactions, serum alanine aminotransferase (ALT) or aspartate aminotransferase values Grade >2 or total bilirubin greater than the upper limit of normal (ULN), chronic hepatitis B (+HbsAg or +HBV DNA in plasma), hepatitis C, or other known active or chronic liver disease, history of pancreatitis or elevated lipase (≥1.5 above the ULN) or triglyceride level >500 mg/dL, uncontrolled hypertension (persistent measurements over 140/90), bradycardia <50 beats/min, history or presence of a clinically significant abnormal electrocardiogram, history of malignancy or receipt of radiation or cytotoxic chemotherapeutic agents, history of autoimmune or any other disease that required treatment with immunomodulating agents (eg, systemic corticosteroids, interleukins, or interferons) or any agent with known anti-HIV activity (other than antiretrovirals), and use of strong CYP3A4 inducers or inhibitors during the study. Nonsteroidal anti-inflammatory drugs or aspirin use were not exclusionary criteria. Enrollment occurred between February and December of 2016.

Because marketed PDE4 inhibitors (apremilast, roflumilast) carry warning labels regarding depression, suicidal thoughts, or suicidal behavior, candidates who reported depression or were suspected or known to have depression and were on stable antidepressants underwent psychiatric evaluation to determine eligibility, and assessment was repeated during follow-up visits in those deemed eligible to participate.

Participants who met eligibility criteria were randomized 2:1 to study drug CC-11050, 200 mg (2 capsules twice daily [BID]), or placebo (2 capsules BID) both with food, in addition to ART for a period of 12 weeks, taking the first 2 doses on Day 0 (Week 0). Participants returned to clinic for follow-up at weeks 2, 4, 8, 12, and 16. The last day of dosing was the day before the week 12 visit. Participants were instructed to record missed doses, and pill counts were performed and recorded to ascertain drug compliance. At each visit, safety labs and biomarkers associated with inflammation were measured as well as immunophenotyping of T cells and monocytes by flow cytometry.

Study Drug

CC-11050 and placebo were packaged by Celgene Corporation and designee. CC-11050 is primarily metabolized via CYP3A4 enzyme, it is not an inducer or inhibitor, but its pharmacokinetics can be altered by strong CYP3A4 inhibitors or inducers. M15 is a major metabolite of CC-11050 and an inhibitor of the enzymes CYP2C9, 2C19, and 3A4. Persons receiving strong CYP3A4 inhibitors (such as ritonavir or cobicistat) and inducers were excluded from the study. Efavirenz (EFV) is a moderate CYP3A4 inducer and a substrate of CYP2B6 (primary), 2A6, and 3A4 enzymes. Even though it was unlikely to have a significant interaction, we obtained EFV concentration to assess the potential of M15’s effect on EFV pharmacokinetics.

Endpoints

The primary endpoint was frequency and severity of adverse events (AEs) of a 12-week course of CC-11050 in PLWH who had been on ART for ≥1 year and had suppressed plasma viremia. Severity of AE was graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014 (https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables).

Secondary endpoints included the effect of CC-11050 on plasma HIV-1 RNA levels, CD4+, and CD8+ T-cell count and percentage at weeks 2, 4, 8, 12, and 16. We also evaluated CC-11050 concentrations at week 4 (blood was collected before the morning dose on that day) in subjects receiving an EFV-based regimen versus other type of ART regimens, including raltegravir, dolutegravir, or rilpivirine as well as EFV level between patients who received CC-11050 and those who did not.

Exploratory endpoints included the effect of CC-11050 on plasma inflammatory and coagulation biomarkers (ie, TNF-α, IL-6, IL-8, IL-10, IFN-γ, sCD14, CRP, and D-dimer) and on peripheral blood mononuclear cells (PBMCs) and HIV measurements (residual viral replication, cell-associated DNA, and RNA) were evaluated.

Statistics

For comparisons of continuous endpoints within time points, at baseline, or at week 12, t tests, Wilcoxon rank sum tests, and linear regression, including adjustment for baseline level, were used. For comparison of binary endpoints, such as incidence of AEs, Fisher exact tests using central P values were used (R package exact2x2 [19]). In addition, to compare outcome levels over all treatment time points marginally, linear generalized estimating equations (GEE) were used (R package gee [20]); this properly accounts for the repeated measures on the same subject. Differences for all biomarkers and clinical measurements between the arms were investigated by averaging over all treatment weeks, using an unadjusted linear GEE model referred to in the text as “unadjusted GEE”. A linear GEE model adjusted for the baseline value of the biomarkers and week of treatment, referred to in the text as “adjusted GEE” was also used. Finally, we compared the trajectory over the treatment period between the treatment arms using linear GEE model with an interaction of week of treatment and treatment arm which is referred to as “trajectory GEE”. Many tests were performed and P values were not adjusted for multiple comparisons. For this reason, all biomarker results should be considered hypothesis generating or exploratory. All analyses were performed in R.

Cytokine Measurement in Cryopreserved Plasma

Cryopreserved plasma was used from weeks 0, 2, 4, 8, 12, and 16. Plasma levels of IFN-γ (lower limit of detection [LLD] = 0.33 pg/ml), TNF-α (LLD = 0.09 pg/ml), IL-6 (LLD = 0.19 pg/ml), IL-8 (LLD = 0.14 pg/ml), and IL-10 (LLD = 0.09 pg/ml) were measured by electrochemiluminescence using a custom multiplex kit (Meso Scale Discovery, Gaithersburg, MD). Plasma also was measured for sCD14 (LLD = 2.5 E-7 mg/L) using traditional ELISA (enzyme-linked immunosorbent assay) methods (R&D systems, Minneapolis, MN).

Immunophenotyping of PBMCs

Immunophenotyping of peripheral blood drawn into EDTA (ethylenediaminetetracetate) was performed according to the manufacturer’s instructions. Cells were stained with monoclonal antibodies from BD Biosciences (San Jose, CA) then lysed after staining with Optilyse C (Beckman Coulter, Hialeah, FL), washed twice, and resuspended in 500 µl of phosphate-buffered saline (Lonza, Walkersville, MD). Samples were analyzed immediately on a Becton Dickinson FacsCanto II flow cytometer (BD Biosciences, San Jose, CA). BD Multitest 6C TBNK monoclonal antibody (category number 644611, San Jose, CA) contained CD3 FITC (clone SK7), CD16 PE (clone B73.1), CD56 PE (cloneNCAM16.2), CD45 PerCP-Cy™5.5 (clone 2D1), CD4 PE-Cy™7 (clone SK3), CD19 APC (clone SJ25C1), and CD8 APC-Cy7 (clone SK1). BD Multitest 6C TBNK monoclonal antibody (category number 644611, San Jose, CA) was used to determine the CD4⁺ (clone SK3) T cells and the CD8⁺ (SK1) T cells for the patients. Gating using BD FACS DIVA software, version 8.0.1, on CD3⁺CD4⁺ or CD3⁺CD8⁺ cells was used to determine the expression of the HLA-DR⁺ FITC (BD Biosciences [San Jose, CA], clone L243), CD38⁺ PE (BD Biosciences [San Jose, CA], clone HB7), CD27⁺ Pacific Blue (BD Biosciences [San Jose, CA], clone M-T271) and CD45RO⁺ APC (BD Biosciences [San Jose, CA], clone UCHL1) to define activated (HLA-DR⁺CD38⁺), naïve (CD45RO^-CD27⁺), and memory subsets.

PD-L1 expression for monocytes and neutrophils was performed with CD15 FITC (Biolegend, San Diego, CA clone Hl98), CD14 PerCP Cy5.5 (Biolegend, San Diego, CA clone HCD14), and CD274 PD-L1 APC (Biolegend, San Jose, CA clone 29E.2A3). Monocytes and neutrophils were gated using FSC versus SSC followed by CD15 FITC versus CD14 PerCP Cy 5.5.

HIV Measurements

HIV-1 from plasma was isolated by ultracentrifugation, and the resulting pellet was extracted as described in Cline et al [21]. PBMC were subjected to nucleic acid extraction essentially as described for tissues in Simonetti et al [22]. HIV gag DNA and RNA copy numbers were assessed using a multiplexed qPCR assay, as described previously [23]. Plasma HIV-1 is reported as copies/mL of plasma and PBMC-associated HIV-1 DNA or RNA levels are reported as copies/10⁶ cell equivalents, based on 2 copies of the CCR5 gene per haploid cellular genome [24].

RESULTS

Study Participants

Forty-five persons were screened for the study and a total of 30 underwent randomization, from whom 19 went to the CC-11050 group and 11 to the placebo group. Seventeen out of 19 participants in the CC-11050 group and 10 of 11 in the placebo group completed week 16 (Figure 1). The baseline demographic and clinical characteristics are presented in Table 1. The median age was 49 and 48 years in CC-11050 group and placebo groups, respectively. CD4 cell counts, CD8 cell counts, and plasma HIV-RNA levels at entry were similar between the 2 groups. EFV-based ART regimen percentages were 26.3% for the CC-11050 group and 54.5% for the placebo group.

Figure 1. — Consort Diagram. Figure 1 presents the number of patients who were screened, randomized to receive either CC-11050 or placebo, and completed the study. Fifteen participants were excluded during screening. Seventeen out of 19 participants from the CC-11050 group and 10 out of 11 participants from the placebo group completed the 16-week period of the study.

Table 1.

Demographic and Clinical Characteristics of Participants at Baseline

Characteristics	CC-11050 Group (N: 19)	Placebo Group (N:11)
Age–years	48.8 (44.09–53.58)	47.82 (42.00–3.63)
Male sex–N (%)	15 (78.94%)	9 (81.81%)
Race
White–N (%)	9 (47.37%)	7 (63.64%)
African American–N (%)	9 (47.37%)	4 (36.36%)
Asian–N (%)	1 (5.26%)	0 (0%)
Body mass index (kg/m²)	26.11 (24.13–28.08)	28.56 (25.84–31.28)
CD4 cell count (cells/mm³)	469 (355–582)	484 (379–589)
CD8 cell count (cells/mm³)	834 (657–1011)	632 (516–748)
HIV RNA levels (copies/ml)	<40	<40
Hemoglobin (g/dL)	13.11 (12.50–13.72)	13.42 (12.71–14.13)
C-reactive protein (mg/L)	2.65 (1.20–4.09)	3.16 (1.04–5.29)
D-dimer (mg/L) ^a	0.3 (0.27–0.34)	0.3 (0.25–0.36)
ART regimen
NNRTI-based	8 (42.10%)	8 (72.72%)
Efavirenz-based	5 (26.31%)	6 (54.54%)
INSTI-based	11 (57.89%)	3 (27.27%)

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Abbreviations: N, number; NNRTI, non-nucleoside reverse-transcriptase inhibitor; INSTI, integrase strand transfer inhibitor.

^aD-dimer values <0.27 set to 0.26.

Values are presented as median (with the interquartile range in parentheses).

Safety Outcomes

All participants who received at least 1 dose of the study drug or placebo were included in safety analyses. The incidences of AEs were similar overall between the 2 treatment groups during the 12-week, double-blind treatment period. Grade 1 and 2 AEs that were considered possibly or probably related to CC-11050 or placebo are listed in Table 2. There were no Grade 3 or 4 events during the study and there was no AE-associated discontinuation of study drug or placebo. AEs occurring ≥5% of either treatment group are presented in Table 2.

Table 2.

Adverse Events–Related Causality

	Grade 1		Grade 2
	CC-11050 group	Control group	CC-11050 group	Control group
Events	(N = 19)	(N = 11)	(N = 19)	(N = 11)
Gastrointestinal disorders
Diarrhea	4 (21.05%)	5 (45.45%)	1 (5.26%)	0 (0.00%)
Nausea	2 (10.52%)	5 (45.45%)	0 (0.00%)	0 (0.00%)
Abdominal distension	1 (5.26%)	0 (0.00%)	0 (0.00%)	1 (9.09%)
Constipation	0 (0.00%)	0 (0.00%)	0 (0.00%)	1 (9.09%)
Respiratory disorders
Cough	2 (10.52%)	0 (0.00%)	0 (0.00%)	0 (0.00%)
Rhinorrhea	1 (5.26%)	0 (0.00%)	0 (0.00%)	1 (9.09%)
Nasal congestion	1 (5.26%)	0 (0.00%)	1 (5.26%)	0 (0.00%)
Sneezing	1 (5.26%)	0 (0.00%)	0 (0.00%)	0 (0.00%)
Upper respiratory tract infection	0 (0.00%)	1 (9.09%)	1 (5.26%)	0 (0.00%)
Nervous system disorders
Headache	7 (36.84%)	3 (27.27%)	1 (5.26%)	0 (0.00%)
Paresthesia	0 (0.00%)	1 (9.09%)	0 (0.00%)	0 (0.00%)
Cognitive disorder (behavioral/attentional disturbance)	0 (0.00%)	0 (0.00%)	(0.00%)	1 (9.09%)
Psychiatric disorders
Restlessness	2 (10.52%)	0 (0.00%)	0 (0.00%)	0 (0.00%)
Irritability, impatience	0 (0.00%)	1 (9.09%)	0 (0.00%)	0 (0.00%)
Distractibility	0 (0.00%)	1 (9.09%)	0 (0.00%)	0 (0.00%)
General disorders
Decreased appetite	1 (5.26%)	0 (0.00%)	0 (0.00%)	0 (0.00%)
Fatigue	0 (0.00%)	0 (0.00%)	1 (5.26%)	0 (0.00%)
Abnormal laboratory assessments
Lipase increase	2 (10.52%)	0 (0.00%)	1 (5.26%)	0 (0.00%)
Hemoglobin decrease	0 (0.00%)	2 (18.18%)	0 (0.00%)	0 (0.00%)
Blood creatinine increase	1 (5.26%)	0 (0.00%)	0 (0.00%)	1 (9.09%)
ALT increase	1 (5.26%)	0 (0.00%)	0 (0.00%)	0 (0.00%)

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Lipase increase Grade 1: ≥66 and <90 and Grade 2 ≥90 and <180; hemoglobin decrease Grade 1: 9.5-10.4 g/dL; creatinine increase Grade 1: 1.29–1.52 and Grade 2: 1.53 -2.11; and ALT (alanine aminotransferase) increase Grade 1: ≥51 and < 103. No significant differences were noted (all P values > .05).

The most frequent AEs in the CC-11050 group were headache (8 out of 19, 42.1%), diarrhea (5 out of 19, 26.3%), nausea (2 out of 19, 10.5%), cough (2 out of 19, 10.5%), nasal congestion (2 out of 19, 10.5%) and restlessness (2 out of 19, 10.5%). Grade 2 events possibly or probably related to study drug included 1 incidence of each diarrhea, headache, nasal congestion, and upper respiratory infection, and resolved in 4 weeks without medical intervention and despite continued treatment. There was also 1 participant who reported fatigue that resolved within 6 weeks.

Laboratory abnormalities, possibly or probably related to study drug, were infrequent (Table 2), and included increase in lipase (3 out of 19 of CC-11050 group; Grade 1, n = 2; Grade 2, n = 1), increase in creatinine (1 out of 19 of CC-11050 group, Grade 1), and in ALT (1 out of 19 of CC-11050 group, Grade 1). In placebo group, there was 1 case of increased creatinine (Grade 2) and 2 cases of decrease in hemoglobin (Grade 1).

Effect of CC-11050 on Plasma HIV RNA Levels and Immune Cell Subsets

Treatment with CC-11050 did not show any significant effect on plasma HIV-RNA levels averaging over weeks 2–12 in the adjusted, unadjusted GEE model nor in trajectory from week 0 to week 12 compared to placebo group. GEE analysis of CD4+ and CD8+ T-cell counts showed no significant differences between arms. Unadjusted GEE analysis showed a significantly higher CD8% in the CC-11050 group than in the placebo group on average over weeks 2–12 (+6.62, P = .028) (Figure 2A). After adjustment for time in weeks and baseline CD8%, however, this difference did not persist; neither CD4% nor CD8% differed in trajectory over week 0–12.

Figure 2. — (A) Average level of percentage of CD8+ T-cells, (B) percentage of NK cells, (C) IL-8, and (D) IL-6, over all time points during the treatment period (weeks 0–12). Participants were randomized to study drug CC-11050 or placebo (control group) for a period of 12 weeks, taking the first 2 doses on Day 0 (Week 0 visit). Participants returned to clinic for follow-up at weeks 2, 4, 8, 12, and 16. The last day of dosing was the day before the week 12 visit. (A) Unadjusted generalized estimating equations (GEE) analysis showed a significantly higher CD8% in the CC-11050 group than in the control group on average over weeks 2–12 (+6.62, P = .028). (B) In the adjusted GEE model, there was a significant reduction in the percentage of NK cells in the CC-11050 group compared to placebo (-0.14 log or 0.87-fold change in the geometric mean, P value = 0.02). (C) The CC-11050 group had lower level of log10 IL-8 in both unadjusted and adjusted GEE models (0.56 and 0.72-fold change respectively, P = .04, 0.02). (D) The CC-11050 group had higher log10 IL-6 level than the placebo group on average week 2–12 in the adjusted GEE model (+0.17 [1.48-fold change in the geometric mean], P = .03). Overall, there was not any significant difference in trajectory.

At baseline, there were no significant differences in the subsets of T cells and monocytes between the CC-11050 and placebo groups. In the GEE model adjusted for baseline biomarker, group, and week, there was a significant reduction in the percentage of NK cells (CD16+CD56+) in the CC-11050 group compared to placebo (-0.14 log, 0.87-fold, P = .02) (Figure 2B). At week 12, the CC-11050 group had an increase in the percentage of CD8+CD38+HLA/DR+ as compared to the placebo group (+0.195, P = .037), including adjustment for baseline. Finally, the CC-11050 group had a higher percentage of intermediate monocytes than placebo at week 12 (median 58.5% and 50.7% respectively, P = .03), but not at week 16 (Supplementary Table 1).

Effect of CC-11050 on Plasma Biomarkers

At baseline, there were no significant differences between the CC-11050 and placebo group in the levels of measured biomarkers (Supplementary Table 1). Analysis of the average level of biomarkers over the 12-week period showed that the CC-11050 group had lower level of log₁₀ IL-8 in both unadjusted and adjusted GEE models (-0.25 and -0.14, respectively [0.56- and 0.72-fold, respectively; P = .04, .02, respectively]) (Figure 2C), but there was no significant difference in trajectory. Participants in CC-11050 group also had higher log₁₀ IL-6 level than the placebo group on average week 2–12 in the adjusted GEE model (+0.17 [1.48-fold], P = .03) (Figure 2D). There was no significant difference between the groups in IL-6 level in the unadjusted or trajectory GEE models. There were no other significant differences in plasma levels of measured biomarkers between the 2 groups.

Effect of CC-11050 on Plasma HIV and PBMC-Associated HIV-1 DNA and RNA

We evaluated the effect of CC-11050 on residual plasma viremia by single copy assay and also on cell-associated (CA) DNA and RNA in PBMC. Our results showed that 12-week of CC-11050 did not have any significant impact in these virologic measurements. Between CC-11050 group and placebo at week 12, there was a difference of (+)13.85 copies/10⁶ cells (P = .06), (+)19.80 copies/10⁶ cells (P = .64), (+)0.15 copies/mL (P = .87) for CA DNA, CA RNA, and plasma HIV viremia, respectively.

Effect of Co-administration of CC-11050 With EFV-Based ART on CC-11050 and EFV Concentrations

The analysis of concentrations of CC-11050 when co-administered with an EFV-based ART regimen compared with other type of ART regimens showed no significant difference (median 152.4 vs 137.3 ng/mL, P = non-significant, Supplementary Table 2).

We also assessed the concentration of EFV at baseline (before initiation of CC-11050) and at week 4 in participants who received either CC-11050 or placebo. Our data suggest that CC-11050 had no effect on EFV concentrations (Supplementary Table 3). In the placebo+EFV arm there was a higher mean concentration of EFV that was primarily driven by 2 persons who had higher concentrations. Of note, there was significant inter-person variability in the concentration that was not related to CC-11050 administration. Correlations of CC-11050 levels with select biomarkers did not reach statistical significance (Supplementary Table 4).

Discussion

In this phase I, randomized, placebo-controlled clinical study, 19 PLWH who were on ART and had suppressed plasma viremia received a new potent PDE4i, CC-11050, for 12 weeks. To our knowledge, this is the first study assessing the safety of PDE4i in PLWH who have viral suppression while on ART. The most common AEs included headache, diarrhea, nausea, cough, and restlessness. All reported side effects were mild to moderate in severity and resolved without medical intervention and despite continued treatment. This was in accordance with previous studies with CC-11050 and other PDE4i that have shown a similar favorable safety profile [25, 26] with infrequent asymptomatic laboratory abnormalities that resolved before the end of the study.

CC-11050 did not adversely affect well controlled HIV viremia and did not change CD4+ T-cell counts. Our data also suggest that, as anticipated, there was no pharmacokinetic interaction between CC-11050 and EFV levels in those participants co-treated with CC-11050 and EFV suggesting that co-administration would not be problematic.

We also explored the effect of CC-11050 on the levels of soluble and cellular biomarkers of inflammation that have been associated with risk of TB-IRIS development and with residual inflammation on ART. Interestingly, the CC-11050 group demonstrated over the 12-week treatment period a lower level of IL-8. Previous studies have shown an association between elevated IL-8 before ART initiation and the risk of IRIS development as well as increase in IL-8 during TB-IRIS [27–30], and high IL-8 can be associated with innate immune activation known to be predisposed to cardiovascular disease [31]. In contrast to other reports, we did not observe a decrease in other inflammatory cytokines that have been traditionally linked with the pathogenesis of IRIS and serious non-AIDS events [28, 32–37].

People who received CC-11050 had a 1.48-fold higher level of IL-6 compared to the control group over a period of 12 weeks, but there was no significant difference between the groups in IL-6 levels in the unadjusted or trajectory GEE models. Our data also suggested a decrease in NK cells after 12-weeks of CC-11050. Previous studies have shown that HIV⁺/TB⁺ patients who developed IRIS after ART initiation exhibited significantly higher levels of NK-cell degranulation before ART initiation [38]. Interestingly, Conradie and colleagues had previously shown that patients with unmasking TB-IRIS had a higher percentage of activated NK cells as well as increased plasma levels of IL-8 compared with both HIV-positive individuals and MTB-HIV co-infected individuals, and they suggested that IL-8 might be involved in the activation and chemotaxis of NK cells [39]. Although we did not demonstrate any striking changes in the percentages of T-cell and monocyte subsets, it would be interesting to assess the effect of CC-11050 in the functional level of monocytes and T cells in vitro. However, these experiments were beyond the scope of our study.

Our study limitations include its relatively small size and the short period of study drug administration that might have limited detection of important immunologic effects. It is also important to consider that the purpose of this study was primarily to assess the safety of co-administration of a new PDE4i along with ART in well-controlled PLWH. By including individuals with suppressed viremia and relatively low baseline levels of inflammatory markers, without any co-infection or significant comorbidities at baseline, it would not be appropriate to extrapolate these findings to the potential effect of CC-11050 in patients at risk or even with IRIS or at high risk for cardiovascular events and conditions with higher inflammation or tissue remodeling. Recently, Subbian and colleagues showed reduced lung pathology and fibrosis and improvement in bacillary clearance in rabbits treated for 8 weeks with isoniazid and CC-11050, compared to rabbits treated with isoniazid or CC-11050 alone associated with dampened expression of host genes of tissue remodeling, TNF regulation, macrophage activation, and lung inflammation [16–18].

In conclusion, the results of this study demonstrated that CC-11050 is safe and well tolerated in PLWH without interfering with previously well-controlled virologic status. Although this study excluded patients with opportunistic infections or high levels of inflammation, given that our primary goal was to assess the safety in PLWH, it could still provide the basis for further evaluation of clinical efficacy of CC-11050 as potential anti-inflammatory adjuvant strategy.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

ofz246_suppl_supplementary_tables

Click here for additional data file.^{(19.4KB, docx)}

Acknowledgments

Financial support. This work was supported in part by the Intramural Research Program of National Institute of Allergy and Infectious Diseases at the National Institutes of Health. This project was also funded in part with federal funds from the National Cancer Institute of the National Institutes of Health under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

1. Wilson EM, Sereti I. Immune restoration after antiretroviral therapy: the pitfalls of hasty or incomplete repairs. Immunol Rev 2013; 254:343–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
2. Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health during chronic HIV infection. Immunity 2013; 39:633–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Zanni MV, Schouten J, Grinspoon SK, Reiss P. Risk of coronary heart disease in patients with HIV infection. Nat Rev Cardiol 2014; 11:728–41. [DOI] [PubMed] [Google Scholar]
4. Shah S, Ma Y, Scherzer R, et al. Association of HIV, hepatitis C virus and liver fibrosis severity with interleukin-6 and C-reactive protein levels. AIDS 2015; 29:1325–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Gupta SK, Kitch D, Tierney C, et al. ; AIDS Clinical Trials Group Study A5224s Team Markers of renal disease and function are associated with systemic inflammation in HIV infection. HIV Med 2015; 16:591–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Cockerham LR, Siliciano JD, Sinclair E, et al. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells. PLOS ONE 2014; 9:e110731. [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Schuetz A, Deleage C, Sereti I, et al. ; RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLOS Pathog 2014; 10:e1004543. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Teigler JE, Leyre L, Chomont N, et al. ; RV254/RV217 Study Groups Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir size. JCI Insight 2018; 3:pii: 98420. [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol 2010; 159:842–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Schafer PH, Chen P, Fang L, et al. The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1). J Immunol Res 2015; 2015:906349. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Gottlieb AB, Matheson RT, Menter A, et al. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. J Drugs Dermatol 2013; 12:888–97. [PubMed] [Google Scholar]
12. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis 2014; 73:1020–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Cutolo M, Myerson GE, Fleischmann RM, et al. A phase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: results of the PALACE 2 trial. J Rheumatol 2016; 43:1724–34. [DOI] [PubMed] [Google Scholar]
14. Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015; 385:857–66. [DOI] [PubMed] [Google Scholar]
15. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol 2016; 75:494–503.e6. [DOI] [PubMed] [Google Scholar]
16. Subbian S, Tsenova L, Holloway J, et al. Adjunctive phosphodiesterase-4 inhibitor therapy improves antibiotic response to pulmonary tuberculosis in a rabbit model. EBioMedicine 2016; 4:104–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Subbian S, Tsenova L, O’Brien P, et al. Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs. PLOS Pathog 2011; 7:e1002262. [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Subbian S, Tsenova L, O’Brien P, et al. Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology. Am J Pathol 2011; 179:289–301. [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Fay MP, Proschan MA, Brittain E. Combining one-sample confidence procedures for inference in the two-sample case. Biometrics 2015; 71:146–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Generalized Estimation Equation Solver [computer program]. R package version 4.13–19. https://CRAN.R-project.org/package=gee. Published June 29, 2015. Accessed May 25, 2019.
21. Cline AN, Bess JW, Piatak M Jr, Lifson JD. Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS. J Med Primatol 2005; 34:303–12. [DOI] [PubMed] [Google Scholar]
22. Simonetti FR, Sobolewski MD, Fyne E, et al. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc Natl Acad Sci USA 2016; 113:1883–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
23. Somsouk M, Dunham RM, Cohen M, et al. The immunologic effects of mesalamine in treated HIV-infected individuals with incomplete CD4+ T cell recovery: a randomized crossover trial. PLOS ONE 2014; 9:e116306. [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Thomas JA, Gagliardi TD, Alvord WG, et al. Human immunodeficiency virus type 1 nucleocapsid zinc-finger mutations cause defects in reverse transcription and integration. Virology 2006; 353:41–51. [DOI] [PubMed] [Google Scholar]
25. Crowley J, Thaçi D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol 2017; 77:310–317.e1. [DOI] [PubMed] [Google Scholar]
26. Reich K, Gooderham M, Green L, et al. The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol 2017; 31:507–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Grant PM, Komarow L, Lederman MM, et al. Elevated interleukin 8 and T-helper 1 and T-helper 17 cytokine levels prior to antiretroviral therapy in participants who developed immune reconstitution inflammatory syndrome during ACTG A5164. J Infect Dis 2012; 206:1715–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
28. Haridas V, Pean P, Jasenosky LD, et al. ; CAPRI-T (ANRS 12164) Study Team TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB. AIDS 2015; 29:263–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Chakrabarti LA, Boucherie C, Bugault F, et al. ; ANRS 129 BKVIR-CYTOK Study Group Biomarkers of CD4+ T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2014; 28:1593–602. [DOI] [PubMed] [Google Scholar]
30. Goovaerts O, Jennes W, Massinga-Loembé M, et al. ; TB-IRIS Study Group LPS-binding protein and IL-6 mark paradoxical tuberculosis immune reconstitution inflammatory syndrome in HIV patients. PLOS ONE 2013; 8:e81856. [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Jalbert E, Crawford TQ, D’Antoni ML, et al. IL-1Β enriched monocytes mount massive IL-6 responses to common inflammatory triggers among chronically HIV-1 infected adults on stable anti-retroviral therapy at risk for cardiovascular disease. PLOS ONE 2013; 8:e75500. [DOI] [PMC free article] [PubMed] [Google Scholar]
32. Barber DL, Mayer-Barber KD, Antonelli LR, et al. Th1-driven immune reconstitution disease in Mycobacterium avium-infected mice. Blood 2010; 116:3485–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Boulware DR, Hullsiek KH, Puronen CE, et al. ; INSIGHT Study Group Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. J Infect Dis 2011; 203:1637–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Musselwhite LW, Andrade BB, Ellenberg SS, et al. Vitamin D, D-dimer, Interferon γ, and sCD14 levels are independently associated with immune reconstitution inflammatory syndrome: a prospective, international study. EBioMedicine 2016; 4:115–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Grant PM, Komarow L, Lederman MM, et al. Elevated interleukin 8 and T-helper 1 and T-helper 17 cytokine levels prior to antiretroviral therapy in participants who developed immune reconstitution inflammatory syndrome during ACTG A5164. J Infect Dis 2012; 206:1715–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
36. Sereti I, Rodger AJ, French MA. Biomarkers in immune reconstitution inflammatory syndrome: signals from pathogenesis. Curr Opin HIV AIDS 2010; 5:504–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Tan HY, Yong YK, Andrade BB, et al. Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2015; 29:421–31. [DOI] [PubMed] [Google Scholar]
38. Pean P, Nerrienet E, Madec Y, et al. ; Cambodian Early versus Late Introduction of Antiretroviral Drugs (CAMELIA) study team Natural killer cell degranulation capacity predicts early onset of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients with tuberculosis. Blood 2012; 119:3315–20. [DOI] [PubMed] [Google Scholar]
39. Conradie F, Foulkes AS, Ive P, et al. Natural killer cell activation distinguishes Mycobacterium tuberculosis-mediated immune reconstitution syndrome from chronic HIV and HIV/MTB coinfection. J Acquir Immune Defic Syndr 2011; 58:309–18. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ofz246_suppl_supplementary_tables

Click here for additional data file.^{(19.4KB, docx)}

[CIT0001] 1. Wilson EM, Sereti I. Immune restoration after antiretroviral therapy: the pitfalls of hasty or incomplete repairs. Immunol Rev 2013; 254:343–54. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0002] 2. Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health during chronic HIV infection. Immunity 2013; 39:633–45. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0003] 3. Zanni MV, Schouten J, Grinspoon SK, Reiss P. Risk of coronary heart disease in patients with HIV infection. Nat Rev Cardiol 2014; 11:728–41. [DOI] [PubMed] [Google Scholar]

[CIT0004] 4. Shah S, Ma Y, Scherzer R, et al. Association of HIV, hepatitis C virus and liver fibrosis severity with interleukin-6 and C-reactive protein levels. AIDS 2015; 29:1325–33. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0005] 5. Gupta SK, Kitch D, Tierney C, et al. ; AIDS Clinical Trials Group Study A5224s Team Markers of renal disease and function are associated with systemic inflammation in HIV infection. HIV Med 2015; 16:591–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0006] 6. Cockerham LR, Siliciano JD, Sinclair E, et al. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells. PLOS ONE 2014; 9:e110731. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0007] 7. Schuetz A, Deleage C, Sereti I, et al. ; RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLOS Pathog 2014; 10:e1004543. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0008] 8. Teigler JE, Leyre L, Chomont N, et al. ; RV254/RV217 Study Groups Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir size. JCI Insight 2018; 3:pii: 98420. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0009] 9. Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol 2010; 159:842–55. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0010] 10. Schafer PH, Chen P, Fang L, et al. The pharmacodynamic impact of apremilast, an oral phosphodiesterase 4 inhibitor, on circulating levels of inflammatory biomarkers in patients with psoriatic arthritis: substudy results from a phase III, randomized, placebo-controlled trial (PALACE 1). J Immunol Res 2015; 2015:906349. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0011] 11. Gottlieb AB, Matheson RT, Menter A, et al. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. J Drugs Dermatol 2013; 12:888–97. [PubMed] [Google Scholar]

[CIT0012] 12. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis 2014; 73:1020–6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0013] 13. Cutolo M, Myerson GE, Fleischmann RM, et al. A phase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: results of the PALACE 2 trial. J Rheumatol 2016; 43:1724–34. [DOI] [PubMed] [Google Scholar]

[CIT0014] 14. Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015; 385:857–66. [DOI] [PubMed] [Google Scholar]

[CIT0015] 15. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol 2016; 75:494–503.e6. [DOI] [PubMed] [Google Scholar]

[CIT0016] 16. Subbian S, Tsenova L, Holloway J, et al. Adjunctive phosphodiesterase-4 inhibitor therapy improves antibiotic response to pulmonary tuberculosis in a rabbit model. EBioMedicine 2016; 4:104–14. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0017] 17. Subbian S, Tsenova L, O’Brien P, et al. Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs. PLOS Pathog 2011; 7:e1002262. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0018] 18. Subbian S, Tsenova L, O’Brien P, et al. Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology. Am J Pathol 2011; 179:289–301. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0019] 19. Fay MP, Proschan MA, Brittain E. Combining one-sample confidence procedures for inference in the two-sample case. Biometrics 2015; 71:146–56. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0020] 20.Generalized Estimation Equation Solver [computer program]. R package version 4.13–19. https://CRAN.R-project.org/package=gee. Published June 29, 2015. Accessed May 25, 2019.

[CIT0021] 21. Cline AN, Bess JW, Piatak M Jr, Lifson JD. Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS. J Med Primatol 2005; 34:303–12. [DOI] [PubMed] [Google Scholar]

[CIT0022] 22. Simonetti FR, Sobolewski MD, Fyne E, et al. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc Natl Acad Sci USA 2016; 113:1883–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0023] 23. Somsouk M, Dunham RM, Cohen M, et al. The immunologic effects of mesalamine in treated HIV-infected individuals with incomplete CD4+ T cell recovery: a randomized crossover trial. PLOS ONE 2014; 9:e116306. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0024] 24. Thomas JA, Gagliardi TD, Alvord WG, et al. Human immunodeficiency virus type 1 nucleocapsid zinc-finger mutations cause defects in reverse transcription and integration. Virology 2006; 353:41–51. [DOI] [PubMed] [Google Scholar]

[CIT0025] 25. Crowley J, Thaçi D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol 2017; 77:310–317.e1. [DOI] [PubMed] [Google Scholar]

[CIT0026] 26. Reich K, Gooderham M, Green L, et al. The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol 2017; 31:507–17. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0027] 27. Grant PM, Komarow L, Lederman MM, et al. Elevated interleukin 8 and T-helper 1 and T-helper 17 cytokine levels prior to antiretroviral therapy in participants who developed immune reconstitution inflammatory syndrome during ACTG A5164. J Infect Dis 2012; 206:1715–23. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0028] 28. Haridas V, Pean P, Jasenosky LD, et al. ; CAPRI-T (ANRS 12164) Study Team TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB. AIDS 2015; 29:263–73. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0029] 29. Chakrabarti LA, Boucherie C, Bugault F, et al. ; ANRS 129 BKVIR-CYTOK Study Group Biomarkers of CD4+ T-cell activation as risk factors for tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2014; 28:1593–602. [DOI] [PubMed] [Google Scholar]

[CIT0030] 30. Goovaerts O, Jennes W, Massinga-Loembé M, et al. ; TB-IRIS Study Group LPS-binding protein and IL-6 mark paradoxical tuberculosis immune reconstitution inflammatory syndrome in HIV patients. PLOS ONE 2013; 8:e81856. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0031] 31. Jalbert E, Crawford TQ, D’Antoni ML, et al. IL-1Β enriched monocytes mount massive IL-6 responses to common inflammatory triggers among chronically HIV-1 infected adults on stable anti-retroviral therapy at risk for cardiovascular disease. PLOS ONE 2013; 8:e75500. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0032] 32. Barber DL, Mayer-Barber KD, Antonelli LR, et al. Th1-driven immune reconstitution disease in Mycobacterium avium-infected mice. Blood 2010; 116:3485–93. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0033] 33. Boulware DR, Hullsiek KH, Puronen CE, et al. ; INSIGHT Study Group Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. J Infect Dis 2011; 203:1637–46. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0034] 34. Musselwhite LW, Andrade BB, Ellenberg SS, et al. Vitamin D, D-dimer, Interferon γ, and sCD14 levels are independently associated with immune reconstitution inflammatory syndrome: a prospective, international study. EBioMedicine 2016; 4:115–23. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0035] 35. Grant PM, Komarow L, Lederman MM, et al. Elevated interleukin 8 and T-helper 1 and T-helper 17 cytokine levels prior to antiretroviral therapy in participants who developed immune reconstitution inflammatory syndrome during ACTG A5164. J Infect Dis 2012; 206:1715–23. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0036] 36. Sereti I, Rodger AJ, French MA. Biomarkers in immune reconstitution inflammatory syndrome: signals from pathogenesis. Curr Opin HIV AIDS 2010; 5:504–10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0037] 37. Tan HY, Yong YK, Andrade BB, et al. Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2015; 29:421–31. [DOI] [PubMed] [Google Scholar]

[CIT0038] 38. Pean P, Nerrienet E, Madec Y, et al. ; Cambodian Early versus Late Introduction of Antiretroviral Drugs (CAMELIA) study team Natural killer cell degranulation capacity predicts early onset of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients with tuberculosis. Blood 2012; 119:3315–20. [DOI] [PubMed] [Google Scholar]

[CIT0039] 39. Conradie F, Foulkes AS, Ive P, et al. Natural killer cell activation distinguishes Mycobacterium tuberculosis-mediated immune reconstitution syndrome from chronic HIV and HIV/MTB coinfection. J Acquir Immune Defic Syndr 2011; 58:309–18. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

A Phase I, Randomized, Controlled Clinical Study of CC-11050 in People Living With HIV With Suppressed Plasma Viremia on Antiretroviral Therapy (APHRODITE)

Afroditi Boulougoura

Erin Gabriel

Elizabeth Laidlaw

Vikram Khetani

Ken Arakawa

Jeanette Higgins

Adam Rupert

Robert J Gorelick

Keith Lumbard

Alice Pau

April Poole

Angela Kibiy

Princy Kumar

Irini Sereti

Abstract

Objective

Method

Results

Conclusions

Introduction

METHODS

Study Design

Study Drug

Endpoints

Statistics

Cytokine Measurement in Cryopreserved Plasma

Immunophenotyping of PBMCs

HIV Measurements

RESULTS

Study Participants

Figure 1.

Table 1.

Safety Outcomes

Table 2.

Effect of CC-11050 on Plasma HIV RNA Levels and Immune Cell Subsets

Figure 2.

Effect of CC-11050 on Plasma Biomarkers

Effect of CC-11050 on Plasma HIV and PBMC-Associated HIV-1 DNA and RNA

Effect of Co-administration of CC-11050 With EFV-Based ART on CC-11050 and EFV Concentrations

Discussion

Supplementary Data

Acknowledgments

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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