Interleukin-2 therapy in patients with HIV infection

BACKGROUND Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].

Pulmonary Langerhans Cell Histiocytosis with Lytic Bone Involvement in an Adult Smoker: Regression following Smoking Cessation

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the proliferation and dissemination of histiocytes. These in turn may cause symptoms ranging from isolated, infiltrative lesions to severe multisystem disease. Pulmonary Langerhans cell histiocytosis (PLCH) presents as a localized polyclonal proliferation of Langerhans cells in the lungs causing bilateral cysts and fibrosis. In adults, this rare condition is considered a reactive process associated with cigarette smoking. Recently, clonal proliferation has been reported with the presence of BRAF V600E oncogenic mutation in a subset of PLCH patients. Spontaneous resolution was described; however, based on case series, smoking cessation remains the most effective way to achieve complete remission and prevent long term complications related to tobacco. Herein, we report the case of an adult woman with biopsy-proven PLCH presenting with thoracic (T8) vertebral bone destruction. Both the lung and the bone diseases regressed following smoking cessation, representing a rare case of synchronous disseminated PCLH with bone localization. This observation underscores the contribution of cigarette smoking as a systemic trigger of both pulmonary and extrapulmonary bone lesions. A review of similar cases in the literature is also presented

The Relationship between Visceral Adiposity and Nonalcoholic Fatty Liver Disease Diagnosed by Controlled Attenuation Parameter in People with HIV: A Pilot Study

Background: Fat alterations are frequent in people with HIV (PWH) and predict worse cardiometabolic outcomes. Visceral adipose tissue (VAT) is associated with ectopic fat accumulation in the liver. We aimed to investigate nonalcoholic fatty liver disease (NAFLD) diagnosed by controlled attenuation parameter (CAP) as a potential marker of visceral adiposity in PWH. Methods: We conducted a prospective pilot study of HIV mono-infected patients undergoing metabolic characterization and paired CAP measured by transient elastography with dual-energy X-ray absorptiometry (DEXA) scan. NAFLD was defined as CAP >= 285 dB/m, in absence of alcohol abuse. Excess visceral adiposity was defined as VAT > 1.32 Kg. Pairwise correlation, area under the curve (AUC) and logistic regression analysis were employed to study the association between VAT and CAP. Results: Thirty patients were included, of whom 50% had NAFLD. CAP was correlated with VAT (r = 0.650, p < 0.001) measured by DEXA scan. After adjusting for duration of HIV infection, body mass index and waist circumference, CAP remained the only independent predictor of excess VAT (adjusted odds ratio 1.05, 95% confidence interval [CI] 1.01-1.10). The AUC analysis determined CAP had excellent performance to diagnose excess VAT (AUC 0.92, 95% CI 0.81-1.00), higher than BMI and waist circumference. The optimized CAP cut-off to diagnose excess VAT was 266 dB/m, with a sensitivity of 88.3% and a specificity of 84.6%. Conclusions: NAFLD diagnosed by CAP is associated with VAT in PWH independently of anthropometric measures of obesity. CAP may be a potential diagnostic marker of visceral adiposity in the practice of HIV medicine

Drug-microbiota interactions and treatment response: Relevance to rheumatoid arthritis

Knowledge about associations between changes in the structure and/or function of intestinal microbes (the microbiota) and the pathogenesis of various diseases is expanding. However, interactions between the intestinal microbiota and different pharmaceuticals and the impact of these on responses to treatment are less well studied. Several mechanisms are known by which drug-microbiota interactions can influence drug bioavailability, efficacy, and/or toxicity. This includes direct activation or inactivation of drugs by microbial enzymes which can enhance or reduce drug effectiveness. The extensive metabolic capabilities of the intestinal microbiota make it a hotspot for drug modification. However, drugs can also influence the microbiota profoundly and change the outcome of interactions with the host. Additionally, individual microbiota signatures are unique, leading to substantial variation in host responses to particular drugs. In this review, we describe several known and emerging examples of how drug-microbiota interactions influence the responses of patients to treatment for various diseases, including inflammatory bowel disease, type 2 diabetes and cancer. Focussing on rheumatoid arthritis (RA), a chronic inflammatory disease of the joints which has been linked with microbial dysbiosis, we propose mechanisms by which the intestinal microbiota may affect responses to treatment with methotrexate which are highly variable. Furthering our knowledge of this subject will eventually lead to the adoption of new treatment strategies incorporating microbiota signatures to predict or improve treatment outcomes

LILAC pilot study : effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

Background: Chronic inflammation and residual HIV transcription persist in people living with HIV (PLWH) receiving antiretroviral therapy (ART), thus increasing the risk of developing non-AIDS co-morbidities. The mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism and HIV transcription, and therefore represents an interesting novel therapeutic target. Methods: The LILAC pilot clinical trial, performed on non-diabetic ART-treated PLWH with CD4+ /CD8+ T-cell ratios <0.8, evaluated the effects of metformin (12 weeks oral administration; 500-850 mg twice daily), an indirect mTOR inhibitor, on the dynamics of immunological/virological markers and changes in mTOR activation/phosphorylation in blood collected at Baseline, Week 12, and 12 weeks after metformin discontinuation (Week 24) and sigmoid colon biopsies (SCB) collected at Baseline and Week 12. Findings: CD4+ T-cell counts, CD4+ /CD8+ T-cell ratios, plasma markers of inflammation/gut damage, as well as levels of cell-associated integrated HIV-DNA and HIV-RNA, and transcriptionally-inducible HIV reservoirs, underwent minor variations in the blood in response to metformin. The highest levels of mTOR activation/ phosphorylation were observed in SCB at Baseline. Consistently, metformin significantly decreased CD4+ Tcell infiltration in the colon, as well as mTOR activation/phosphorylation, especially in CD4+ T-cells expressing the Th17 marker CCR6. Also, metformin decreased the HIV-RNA/HIV-DNA ratios, a surrogate marker of viral transcription, in colon-infiltrating CD4+ T-cells of 8/13 participants

Material deprivation is associated with liver stiffness and liver-related outcomes in people with HIV

Background: Socioeconomic status (SES) is a driver of health disparities and chronic diseases. People with HIV (PWH) are at risk for chronic liver diseases. We evaluated the association between low SES and hepatic outcomes in PWH. Methods: We included PWH from a prospective cohort. SES was assessed by the Pampalon material and social deprivation index to classify the cohort into quintiles of deprivation. Multivariable linear regression was used to investigate associations of material and social deprivation with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) as markers of hepatic fibrosis and steatosis, respectively. Incidence of outcomes was evaluated through survival analysis. Results: Among the 804 PWH included, 45% and 72% were living in areas of the highest material and social deprivation, respectively. Materially deprived PWH were more frequently female and of non-white ethnicity and had higher prevalence of metabolic comorbidities. After adjustments, material deprivation correlated with increased LSM (β = 1.86, 95% CI 0.53–3.17) but not with CAP (β = 6.47, 95% CI −5.55–18.49). Patients were observed for a median follow-up of 3.8 years. Incidence of liver-related events was higher in most materially deprived compared to most privileged PWH (hazard ratio 3.03, 95% CI 1.03–8.92), while there was no difference in extrahepatic outcomes or all-cause mortality. Social deprivation showed no association with either LSM or clinical outcomes. Conclusions: Living in materially deprived neighbourhoods as a proxy for lower SES, is associated with LSM and liver-related events in PWH. Future strategies should explore mechanisms underlying these relationships and whether enhanced material security improves hepatic outcomes

Ileal immune tonus is a prognosis marker of proximal colon cancer in mice and patients

Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum-tumor axis, influencing clinical outcome