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Nicholas Giustini, Lyudmila Bazhenova UCSD Moores Cancer Center, Department of Hematology and Oncology, 3855 Health Sciences Drive MC #0987, La Jolla, CA, 92093-0829, USACorrespondence: Nicholas Giustini 3855 Health Sciences Drive #0829, La Jolla, CA, 92093-0829 Email ngiustini@health.ucsd.eduAbstract: Immunotherapy plays a central role in the treatment of NSCLC and biomarkers predicting response to ICIs are valuable therapeutic tools. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is integral in therapy selection as its positive predictive nature to ICIs in the metastatic setting is well documented. Tumor mutational burden (TMB) has undergone much study and, while results are somewhat mixed, there is evidence for its positive predictive value with ICI use. Additional markers such as tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), mismatch repair (MMR) and microsatellite instability (MSI), somatic mutations, neutrophil to leukocyte ratio (NLR), smoking history, medication history, and immune-related adverse event (irAE) development can further guide clinicians.Keywords: NSCLC, immunotherapy, biomarkers

Background: People with HIV are both at elevated risk of lung cancer and at high risk of multimorbidity, which makes shared decision-making (SDM) for lung cancer screening (LCS) in people with HIV complex. Currently no known tools have been adapted for SDM in people with HIV., Research Question: Can an SDM decision aid be adapted to include HIV-specific measures with input from both people with HIV and their providers?, Study Design and Methods: This study used qualitative methods including focus groups of people with HIV and interviews with HIV care providers to adapt and iterate an SDM tool for people with HIV. Eligible participants were those with HIV enrolled in an HIV primary care clinic who met age and smoking eligibility criteria for LCS and HIV care providers at the clinic. Both the focus groups and interviews included semistructured discussions of SDM and decision aid elements for people with HIV. We used a framework-guided thematic analysis, mapping themes onto the Health Equity Implementation framework., Results: Forty-three people with HIV participated in eight focus groups; 10 providers were interviewed. Key themes from patients included broad interest in adapting LCS SDM specifically for people with HIV, a preference for clear LCS recommendations, and the need for positive framing emphasizing survival. Providers were enthusiastic about personalized LCS risk assessments and point-of-care tools. Both patients and providers gave mixed views on the usefulness of HIV-specific risk measures in patient-facing tools. Themes were used to adapt a personalized and flexible SDM tool for LCS in people with HIV., Interpretation: People with HIV and providers were enthusiastic about specific tools for SDM that are personalized and tailored for people with HIV, that make recommendations, and that inform LCS decision-making. Divergent views on presenting patient-facing quantitative risk assessments suggests that these elements could be optional but available for review. This tool may have usefulness in complex decision-making for LCS in this population and currently is being evaluated in a pilot prospective trial.

Purpose: Sexual and gender minoritized (SGM) populations face health disparities along the cancer care continuum, although attempts to define these disparities are limited by a lack of comprehensive sexual orientation and gender identity (SOGI) data collection. The objective of this study was to interview a diverse group of stakeholders to understand attitudes, barriers, and facilitators to inform data collection approaches in a cancer care setting. Methods: This was a qualitative study conducted from March to July 2023 with paired surveys of stakeholders including patients, caregivers, providers, and cancer registry staff. Twenty participants across these categories, including half who identified as SGM, completed surveys and interviews. Qualitative data were reduced to themes with exemplar quotations using rapid qualitative analysis methods and compared to survey data. Results: Themes revealed general support for SOGI data collection as part of holistic cancer care, and all participants acknowledged that specific SOGI-related information, particularly correct pronoun usage, was essential to inform patient-centered care. Themes revealed tensions around optimal SOGI data collection methods, mixed opinions on the relevance of sexual orientation, experiences of discrimination and discomfort related to SOGI, and limited acknowledgment of population benefits of SOGI data collection. Conclusion: Themes demonstrated overall support for SOGI data collection but also revealed several barriers, such as a lack of recognition of population benefits and experiences of discrimination and discomfort, that will need to be addressed to comprehensively collect these data. Based on diverse preferences and limitations of all methods of collection, a multimodal approach may be needed to optimize completion.

Background: People with HIV are at increased risk for lung cancer and multimorbidity, complicating the balance of risks and benefits of lung cancer screening. We previously adapted Decision Precision (screenlc.com) to guide shared decision-making for lung cancer screening in people with HIV., Research Question: Does an HIV-adapted and personally tailored decision aid improve shared decision-making regarding lung cancer screening in people with HIV as measured by knowledge, decisional conflict, and acceptability?, Study Design and Methods: This was a single-arm pilot trial of the decision aid in 40 participants with HIV eligible for lung cancer screening. The decision aid included personalized screening recommendations and HIV-specific, 5-year risk estimates of lung cancer and all-cause mortality. Participants reviewed the decision aid at shared decision-making visits and completed previsit and postvisit surveys with measures of knowledge about lung cancer screening, acceptability, and decisional conflict., Results: The 40 enrolled participants were a median age of 62 years, 60% currently smoked, and they had median 5-year risks of lung cancer and all-cause mortality of 2.0% (IQR, 1.4%-3.3%) and 4.1% (IQR, 3.3%-7.9%), respectively. Personalized recommendations included "Encourage Screening" for 53% of participants and "Preference Sensitive" recommendations for the remainder. Participants showed improvement in two validated knowledge measures with relative improvement of 60% (P < 0.001) on the 12-question lung cancer screening knowledge test and 27% (P < .001) on the seven-question lung cancer screening knowledge score, with significant improvement on questions regarding false-positive and false-negative findings, incidental findings, lung cancer-specific mortality benefit, and the possible harms of screening. Participants reported low scores on the decisional conflict scale (median score, 0; interquartile range, 0-5) and high acceptability. Ninety percent of patients ultimately underwent screening within 1 month of the visit., Interpretation: In our study, this HIV-adapted and personally tailored decision aid improved participants' knowledge of risks, benefits, and characteristics of screening with low decisional conflict and high acceptability. Our results indicate that this decision aid can enable high-quality shared decision-making in this high-risk population., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04682301; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: M. T. reports unrelated consultation fees from G02 Foundation. None declared (N. R. M., K. C., M. S., J. Z. B., M. C. B., B. J. W., N. G., T. C., K. Durette, K. DeCell)., (Copyright © 2024 American College of Chest Physicians. All rights reserved.)

Introduction: People with HIV are at higher risk of lung cancer; however, there is limited research on attitudes, barriers, and facilitators to lung cancer screening in people with HIV. The objective of this study was to understand the perspectives on lung cancer screening among people with HIV and their providers., Methods: Surveys of people with HIV and HIV-care providers were complemented by qualitative focus groups and interviews designed to understand the determinants of lung cancer screening in people with HIV. Participants were recruited through an academic HIV clinic in Seattle, WA. Qualitative guides were developed by integrating the Consolidated Framework for Implementation Research and the Tailored Implementation of Chronic Diseases checklist. Themes that emerged from thematic analyses of qualitative data were compared with surveys in joint displays. All study components were conducted between 2021 and 2022., Results: Sixty-four people with HIV completed surveys, and 43 participated in focus groups. Eleven providers completed surveys, and 10 were interviewed for the study. Themes from joint displays show overall enthusiasm for lung cancer screening among people with HIV and their providers, particularly with a tailored and evidence-based approach. Facilitators in this population may include longstanding engagement with providers and health systems and an emphasis on survivorship through preventive healthcare interventions. People with HIV may also face barriers acknowledged by providers, including a high level of medical comorbidities and competing issues such as substance abuse, mental health concerns, and economic instability., Conclusions: This study reveals that people with HIV and their providers have overall enthusiasm toward screening. However, tailored interventions may be needed to overcome specific barriers, including complex decision making in the setting of medical comorbidity and patient competing issues., (Copyright © 2023 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction : Alectinib is a second-generation inhibitor of anaplastic lymphoma kinase (ALK) and RET. Phase III clinical trials have established its superiority to crizotinib in the first-line ALK inhibitor-naïve setting. Studies also support its use over chemotherapy in the post-crizotinib setting. It is currently one of several FDA- and EMA-approved ALK inhibitors, and it is listed as a preferred initial therapy for treatment-naïve ALK-positive non-small cell lung cancer (NSCLC). Areas covered : Herein, the authors provide the reader with details of the chemical structure, pharmacologic properties, resistance mutations, phase I, II, and III clinical trials, and safety profile of alectinib. Furthermore, the authors provide the reader with the expert opinion and future perspectives on the drug. Expert opinion : Alectinib compares favorably to other second-generation ALK inhibitors with regards to safety, tolerability, and efficacy. Based on currently available data, it is an appropriate first-line option. Ongoing studies will better resolve the ideal sequencing of ALK inhibitors in the treatment of ALK-positive NSCLC.

Aim: Chronic immune activation and poor T-cell immune response are strongly associated with disease progression and pathogenesis of both hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-1 infections. Little is known about the impact of anti-HCV Interferon (IFN)-free direct-acting antiviral (DAA) therapy on the systemic T-cells activation and patterns of peripheral T-cells producing pro-inflammatory cytokines., Patients and Methods: Forty-five subjects including 18 HCV mono-infected, 17 HCV/HIV-1 co-infected patients under antiretroviral therapy (ART), and 10 healthy controls (HCs) were recruited. Blood samples were collected at baseline (T0) and 12 weeks after the end of DAA therapy (T1). Cell phenotypes (CD3, CD4, CD8), activation markers (CD38 and HLA-DR), and frequency of IFN-γ, interleukin (IL)-17, and IL-22 producing CD4+ and CD8+ T-cells were measured by flow cytometry. Plasma levels of related cytokines were also measured by enzyme-linked immunosorbent assay (ELISA)., Results: Both HCV, and HCV/HIV-1 patients before and after therapy, showed significant higher percentages of any T-cell subset expressing CD38 and/or HLA-DR compared to HCs. No differences were observed in T-cells activation at T1 compared to T0 in patient groups, and when HCV patients were compared to HCV/HIV-1 group (P>0.05). After therapy, the potential of total circulating T helper (Th) and T cytotoxic (Tc) cells producing IFN-γ, IL-17, and IL-22 were increased. Plasma level of IFN-γ at baseline was showed difference compared to HCs, and significantly reduced after therapy (P<0.05)., Conclusion: Total T-cells immune response enhances after therapy, however, the state of immune activation may remain elevated for a longtime after the end of treatment and contribute to post-Sustained Virologic Response (SVR) consequences., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Raltegravir (RAL) is considered one of the better-tolerated antiretroviral medications, due to limited side effects and minimal drug-drug interactions. Matherials and Methods: We retrospectively evaluated 96 HIV+, over 60 years old, experienced patients who had switched from any antiretroviral drug to raltegravir-based nuc-sparing or standard nucleoside-backbone regimens. A control group with patients aged under 60 years old was included., Results: The median age of the patients was 66 years (IQR 10.5) (77 M, 19 F); the median time horizon of follow-up was 4 years (IQR 5). HIV-RNA at baseline was undetectable for more than 6 months in most of the patients. Median CD4+ count was 453 cells/mmc (IQR 379). 49 patients had AIDS history. All the patients were assuming concomitant medications. No adverse effect attributed to the use of raltegravir was reported in the medical records. Only 2 patients presented virological failure, whereas viremic blips were observed in 10 patients. After switching to RAL-containing regimens triglycerides values showed a statistically significant reduction from a median value of 172 (IQR 105.5) mg/dl to 129 mg/dl (IQR 73) (p=0,0001). Switching to a standard regimens was associated with a marked reduction of triglycerides. Cholesterol levels were reduced at the time of follow-up (T2) but no significant modifications were observed when patients which had introduced drugs to treat dislypidemia were removed from the analysis; in contrast, triglycerides reduction was also confirmed in this sub-group. Patients presented higher levels of CD4+ at T2 and reduced platelet count [from 230 300/mmc (SD 123 527) to 197 125/mmc (SD 66 377), p=0,04]. Similar trends were observed in younger patients., Conclusion: RAL-containing regimens are safe and highly effective in the older population. RALtreatment is associated with the reduction of triglycerides and platelets count in the older population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: HIV infection is characterized by a persistent immune activation associated to a compromised gut barrier immunity and alterations in the profile of the fecal flora linked with the progression of inflammatory symptoms. The effects of high concentration multistrain probiotic (Vivomixx®, Viale del Policlinico 155, Rome, Italy in EU; Visbiome®, Dupont, Madison, Wisconsin in USA) on several aspects of intestinal immunity in ART-experienced HIV-1 patients was evaluated., Methods: A sub-study of a longitudinal pilot study was performed in HIV-1 patients who received the probiotic supplement twice a day for 6 months (T6). T-cell activation and CD4+ and CD8+ T-cell subsets expressing IFNγ (Th1, Tc1) or IL-17A (Th17, Tc17) were stained by cytoflorimetric analysis. Histological and immunohistochemical analyses were performed on intestinal biopsies while enterocytes apoptosis index was determined by TUNEL assay., Results: A reduction in the frequencies of CD4 + and CD8 + T-cell subsets, expressing CD38 + , HLA-DR + , or both, and an increase in the percentage of Th17 cell subsets, especially those with central or effector memory phenotype, was recorded in the peripheral blood and in gut-associated lymphoid tissue (GALT) after probiotic intervention. Conversely, Tc1 and Tc17 levels remained substantially unchanged at T6, while Th1 cell subsets increase in the GALT. Probiotic supplementation was also associated to a recovery of the integrity of the gut epithelial barrier, a reduction of both intraepithelial lymphocytes density and enterocyte apoptosis and, an improvement of mitochondrial morphology sustained in part by a modulation of heat shock protein 60., Conclusions: These findings highlight the potential beneficial effects of probiotic supplementation for the reconstitution of physical and immunological integrity of the mucosal intestinal barrier in ART-treated HIV-1-positive patients., (© 2017 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.)

Introduction: The gut microbiota is involved in the regulation of cognition, mood, anxiety, and pain, and can impact cognitive functions by producing neuroactive substances or releasing bacterial by-products and metabolites. No information is available on the effects of a probiotic supplementation on brain function of HIV+ subjects. In light of the above considerations, we performed a pilot study in cART-treated HIV-1-positive patients with long-term virologic suppression. The aims were to analyze the effect of high-concentration multistrain probiotic supplementation (Vivomixx®; Visbiome®) on several neurocognitive abilities and to evaluate the safety of this supplementation., Methods: To address those issues, neurocognitive performances were explored by administering neuropsychological tests; moreover, miRNA-29a-c levels were measured in cerebrospinal fluid (CSF) to confirm the persistent undetectable levels of HIV-RNA in the central nervous system after probiotic supplementation., Results: Our results show that the Rey auditory verbal learning test (RAVLT) (immediate and delayed recall), Rey-Osterrieth complex figure test (ROCF) (copy immediate and delayed recall), phonological verbal fluency (PVF) test, Toronto alexithymia scale-20 (Tas-20), State-trait anxiety inventory Y-2 (STAY Y-2), and time and weight estimation test (STEP) scores improved significantly during the study. Moreover, we found unchanged levels, associated to high degree of individual variability, in miRNA-29 levels in CSF collected before and after probiotic supplementation., Conclusions: In conclusion, we observed that HIV patients treated with 6 months of this probiotic supplementation appear to have an improvement in some neurocognitive functions; moreover, this approach is safe and did not modify significantly the levels of miRNA in CSF. Further studies are needed to better understand the contribution of the probiotics in modulating gut-brain-axis in HIV patients.

Background: To date, no data are available regarding the effects of probiotics on the pathway of tryptophan/serotonin metabolism among human immunodeficiency virus (HIV) 1-infected individuals. Because a condition of dysbiosis might be responsible for the altered use of tryptophan described in this population, the aim of this study was to investigate the link between probiotic supplementation and serotonin levels in combined antiretroviral therapy-treated patients and the subsistence of an interplay with inflammation., Methods: We conducted a pilot study that included 8 HIV-positive subjects. We collected blood and fecal samples before and after 6 months of probiotic supplementation, to measure the level of serotonin in serum and tryptophan in stool, the expression of CD38 and HLA-DR on peripheral CD4+ T lymphocytes (as immune activation markers), the expression of indoleamine 2,3-dioxygenase 1 messenger RNA (mRNA) and IFN-γ mRNA (as markers of tryptophan metabolism and systemic inflammation)., Results: After probiotic supplementation, we observed a significant increase in concentration of serum serotonin ( P = .008) and a decreased level of tryptophan in plasma. Moreover, a significant reduction in CD38 and HLA-DR expression on the surface of peripheral CD4+ T cells ( P = .008) and a reduced expression of indoleamine 2,3-dioxygenase 1 mRNA on peripheral blood mononuclear cells ( P = .04) were observed., Conclusions: Considering that this probiotic (Vivomixx® in EU; Visbiome® in USA) has an influence on tryptophan metabolism, larger studies on this topic are needed., Competing Interests: DECLARATION OF CONFLICTING INTERESTS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This study aimed to evaluate the association between the IFNL4 rs368234815 (ΔG/TT) dinucleotide polymorphism and the IFN response during chronic HIV-1 infection. We carried out genotyping analysis and measured the expression of IFN-stimulated genes (ISGs) (myxovirus resistance protein A [MxA], ISG15, ISG56, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like [APOBEC] 3F and APOBEC3G) on peripheral blood mononuclear cells collected from naïve and HAART-treated HIV-1-infected patients. There were no statistically significant differences in endogenous ISGs mRNA levels among HIV-1-positive patients bearing different IFNL4 genotypes, suggesting that ISG expression is independent of the IFNL4 genotype in HIV-1 infection.

Recently the tryptophan pathway has been considered an important determinant of HIV-1 infected patients' quality of life, due to the toxic effects of its metabolites on the central nervous system (CNS). Since the dysbiosis described in HIV-1 patients might be responsible for the microbial translocation, the chronic immune activation, and the altered utilization of tryptophan observed in these individuals, we speculated a correlation between high levels of immune activation markers in the cerebrospinal fluid (CSF) of HIV-1 infected patients and the over-expression of indolamine-2,3-dioxygenase (IDO) at the gut mucosal surface. In order to evaluate this issue, we measured the levels of neopterin in CSF, and the expression of IDO mRNA in gut-associated lymphoid tissue (GALT), in HIV-1-infected patients on effective combined antiretroviral therapy (cART), at baseline and after six months of probiotic dietary management. We found a significant reduction of neopterin and IDO mRNA levels after the supplementation with probiotic. Since the results for the use of adjunctive therapies to reduce the levels of immune activation markers in CSF have been disappointing so far, our pilot study showing the efficacy of this specific probiotic product should be followed by a larger confirmatory trial., Competing Interests: The authors declare no conflict of interest.

HIV infection may enhance immune-activation, while little is known regarding the role of HCV infection. This study investigates the impact of HCV in HIV coinfected patients with undetectable viraemia under HAART on the levels of peripheral T cell's immune-activation. We determined T lymphocytes subsets to characterize immune-activation defined as CD38 and/or HLA-DR expression in chronic monoinfected HCV, HIV, and HIV/HCV coinfected subjects. One hundred and fifty six patients were divided into three groups: (i) 77 HIV+ patients; (ii) 50 HCV+ patients; and (iii) 29 coinfected HIV/HCV patients. The level of CD4(+) was significantly higher in HCV+ than in HIV+ or in coinfected HIV/HCV subjects. The frequencies of CD4(+) CD38(+) /HLA-DR(-) , CD4(+) CD38(-) /HLA-DR(+) and CD4(+) CD38(+) /HLA-DR(+) in HIV+ patients were comparable to those measured in coinfected patients, but statistically higher than those observed in HCV+ subjects. The percentage of CD8(+) was comparable in HIV-1+ patients and coinfected HIV/HCV but the results obtained in both groups were significantly higher compared to the results obtained in HCV patients. The level of CD8(+) CD38(+) /HLA-DR(-) showed values lower in HIV+ patients than in that monoinfected HCV and coinfected HIV/HCV patients. The frequencies of CD8(+) CD38(-) /HLA-DR(+) were higher in HIV+ patients compared to HCV+ and coinfected HIV/HCV patients. HIV/HCV coinfected group showed highest levels of CD8(+) CD38(+) /HLA-DR(+) . HIV plays a pivotal role to determine the immune activation in the host. The role of HCV needs of further investigations but our data show that HCV mainly influences the immune-activation of the pool of CD8, but also probably plays a supporting additive effect on CD4 immune-activation. J. Med. Virol. 88:1347-1356, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Previous studies have reported that protease inhibitors (PIs) can contribute to glycaemic alterations. However, there are few trials examining the direct effect of a single PI. The objective of the study was to evaluate the modifications of glucose and lipid profiles after a switch from lopinavir/ritonavir (LPV/r) to atazanavir, used as ritonavir-boosted (ATV/r) or un-boosted. We conducted a retrospective observational cohort study on the effect of ATV/(r) on glycaemic metabolism (ATAGLU) in patients with undetectable levels of HIV-RNA who switched from LPV/r. In total, 235 patients treated for 48 weeks with LPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) and with undetectable HIV-RNA were included: 134 continued LPV/r after the initial 48 weeks and 101 switched to ATV(/r) (18.3% to ATV; 24.7% to ATV/r). A significant decrease in mean glucose level and insulin resistance was observed in patients who switched to ATV(/r). The mean cholesterol triglyceride levels increased in the LPV/r group and decreased among the patients who switched. A significant increase of CD4 T cells with undetectable levels of HIV-RNA was observed in all groups. The long-term results obtained in this real-life study suggest that patients who have achieved initial suppression on a regimen including LPV/r + two NRTIs can switch to ATV/(r) + two NRTIs with an improvement in lipid and glycaemic metabolism., (© The Author(s) 2015.)

Despite the combined antiretroviral therapy has improved the length and quality of life of HIV infected patients, the survival of these patients is always decreased compared with the general population. This is the consequence of non-infectious illnesses including cardio vascular diseases. In fact large studies have indicated an increased risk of coronary atherosclerotic disease, myocardial infarction even in HIV patients on cART. In HIV infected patients several factors may contribute to the pathogenesis of cardiovascular problems: life-style, metabolic parameters, genetic predisposition, viral factors, immune activation, chronic inflammation and side effects of antiretroviral therapy. The same factors may also contribute to complicate the clinical management of these patients. Therefore, treatment of these non-infectious illnesses in HIV infected population is an emerging challenge for physicians. The purpose of this review is to focus on the new insights in non AIDS-related cardiovascular diseases in patients with suppressed HIV viremia.

Background: HIV infection results in damage to the gastrointestinal (GI) tract, microbial translocation and immune activation. These are not completely normalized with combined antiretroviral therapy (cART). Moreover, increate morbidity and mortality of cART-treated HIV-infected individuals is associated with inflammation., Methods: In order to enhance GI tract immunity, we recruited and treated 20 HIV-infected humans with cART supplemented with probiotics and followed inflammation and immunological parameters (clinical trial number NCT02164344). 11 HIV seronegative subjects were included as control group. The enumeration of CD4+, CD8+, CD38+ and HLA-DR+ lymphocytes were evaluated on peripheral blood; HIV-RNA levels, sCD14, d-dimer, C-reactive protein (CRP) high sensitivity C-reactive protein (hsCRP), IL-6 and Lipopolysaccharide Binding Protein (LBP) were assayed on plasma., Results: We observe that cART does not normalize the levels of immune activation in HIV positive patients anyway inflammation and markers of microbial translocation were significantly reduced with probiotic supplementation. Patients show a clear and statistically significant reduction in the levels of immune activation on CD4 T-lymphocytes, for both markers CD38 and HLA-DR and their simultaneous expression, LBP and hsCRP plasma levels after probiotic diet supplementation settling to values comparable to controls., Conclusions: Supplementing cART with probiotics in HIV-infected individuals may improve GI tract immunity and there by mitigate inflammatory sequelae, ultimately improving prognosis., Trial Registration: ClinicalTrials.gov NCT02164344.

The complex relationship between both the Th1/Th17 and Tc1/Tc17 axis and innate defences in the intestinal mucosa during HIV-1 infection has not been well characterized. This study examined the frequency, phenotype, and functional status of T cell populations in the gut-associated lymphoid tissue and peripheral blood of virologically suppressed HIV-1-infected patients on therapy, focusing on the Th1, Th17, Tc1, and Tc17 cell subsets. We found a persistent immune cell activation (CD38 and HLADR expression) into the GALT despite the higher levels of Th17 and Tc17 in respect to peripheral blood. An upregulation of type I IFN response in GALT compared to the peripheral blood compartment was also recorded. Furthermore, IFN-α/β levels were negatively related to the frequencies of Th1 naïve cells and Tc1 cell subsets (naïve, central memory, and effector memory) in the GALT. In contrast, no relationships between type I IFN response and Th1 or Tc1 cell subsets in peripheral blood compartment and between IFN-α/β and Th17/Tc17 in both GALT and peripheral blood district were recorded. These data indicate that prolonged antiretroviral treatment improves GALT immune function despite the persistence of immune activation and type I IFN response in chronic HIV-1 positive patients.

Introduction: During HIV infection the severe depletion of intestinal CD4+ T-cells is associated with microbial translocation, systemic immune activation, and disease progression. This study examined intestinal and peripheral CD4+ T-cell subsets reconstitution under combined antiretroviral therapy (cART), and systemic immune activation markers., Methods: This longitudinal single-arm pilot study evaluates CD4+ T cells, including Th1 and Th17, in gut and blood and soluble markers for inflammation in HIV-infected individuals before (M0) and after eight (M8) months of cART. From January 2010 to December 2011, 10 HIV-1 naïve patients were screened and 9 enrolled. Blood and gut CD4+ T-cells subsets and cellular immune activation were determined by flow-cytometry and plasma soluble CD14 by ELISA. CD4+ Th17 cells were detected in gut biopsies by immunohistochemistry. Microbial translocation was measured by limulus-amebocyte-lysate assay to detect bacterial lipopolysaccharide (LPS) and PCR Real Time to detect plasma bacterial 16S rDNA., Results: Eight months of cART increased intestinal CD4+ and Th17 cells and reduced levels of T-cell activation and proliferation. The magnitude of intestinal CD4+ T-cell reconstitution correlated with the reduction of plasma LPS. Importantly, the magnitude of Th17 cells reconstitution correlated directly with blood CD4+ T-cell recovery., Conclusion: Short-term antiretroviral therapy resulted in a significant increase in the levels of total and Th17 CD4+ T-cells in the gut mucosa and in decline of T-cell activation. The observation that pre-treatment levels of CD4+ and of CD8+ T-cell activation are predictors of the magnitude of Th17 cell reconstitution following cART provides further rationale for an early initiation of cART in HIV-infected individuals., Trial Registration: ClinicalTrials.gov NCT02097381.

Many sets of data indicate that HIV-infected individuals maintain a low level of chronic immune activation and inflammation even in the presence of effective antiretroviral therapy (ART). This residual immune activation seems to be associated with accelerated aging and an increased incidence of non-AIDS-defining illnesses. Several published studies suggest that physical activity is a beneficial nonpharmacological intervention to reduce chronic inflammation. However, currently available data on the potential benefits of regular physical exercises for HIV-infected individuals are limited. Nonetheless, increasing evidence suggests that the introduction of regular physical exercise in the clinical management of HIV-infected individuals may have a significant positive impact in reducing some of the long-term complications of both infection and ART. Based on a comprehensive review of the existing data, we propose that regular physical exercise should be further studied as a potential antiinflammatory, nonpharmacological approach to be used to treat HIV residual disease and non-AIDS-defining illnesses in ART-treated HIV-infected individuals.

Interleukin-17 (IL-17) is a pro-inflammatory cytokine that is mainly produced by CD4+ T cells. The role of Th17 during the human immunodeficiency virus (HIV)-1 infection is still unclear, but HIV-1 infection can cause a preferential depletion of Th17 cells. It has been shown that IL-15 elicits IL-17 production from human peripheral blood mononuclear cells. We studied the effect of IL-15 stimulation in vitro on IL-17 production from CD4+ mononuclear cells of HIV-infected patients. We observed that IL-15 triggers, in a dose-dependent manner, IL-17 secretion. This effect was blocked by anti-IL-15 monoclonal antibody (P=0.01). Interestingly, IL-17 production was significantly lower in patients with detectable plasma viremia when compared with successfully treated HIV-infected patients (P=0.02) and healthy controls, respectively (P<0.001). We also noticed a significant difference in IL-17 production between naïve HIV-infected patients and patients with virological failure on combined antiretroviral therapy (cART) (P=0.02). Our results suggest that IL-15 can induce IL-17 production from peripheral CD4+ mononuclear cells of HIV-infected patients. Persistent HIV plasma viremia could cause a severe perturbation of IL-17 production from CD4+ mononuclear cells. IL-17 production in HIV-infected patients could be recovered through a sustained suppression of the viral replication in the peripheral blood through cART.