Next-generation sequencing in breast pathology: real impact on routine practice over a decade since its introduction.

The diagnosis, histomolecular classes of breast cancers (luminal A, luminal B, HER2-enriched, and basal-like), and accurate prediction of prognosis are commonly determined using morphological and phenotypical analyses in clinical practice worldwide. Therapeutic strategies are mostly based on the disease stage and molecular subclasses of breast cancer. Targeted therapies, such as anti-HER2s, poly-ADP ribose polymerase inhibitors or, to a lesser extent, phosphatidylinositol 3 kinase inhibitors, have substantially improved breast cancer patient prognosis over the past decades. Human epidermal growth factor receptor 2 (HER2) overexpression is widely determined based on immunohistochemistry, while next-generation sequencing (NGS) is currently employed to assess the presence of molecular alterations, including breast cancer gene 1 (BRCA1) and 2 or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, which are targets of these new approved therapies. In addition, next-generation sequencing (NGS) can aid the pathologist in challenging situations, such as a diagnostic workup for a metastatic carcinoma in lymph nodes of unknown origin, differential diagnosis of spindle cell tumourtumor in the breast between metaplastic carcinoma, malignant PT and sarcoma, o, as well as determining relatedness between primary breast cancers and recurrences. NGS offers a powerful tool that enables the pathologist to combine morphological analyses together with molecular alterations in challenging diagnostic situations.

Nivolumab plus ipilimumab in metastatic uveal melanoma: a real-life, retrospective cohort of 47 patients.

Although combined PD-1/CTLA-4 inhibition showed limited efficacy in single-arm, phase II trials in metastatic uveal melanoma (mUM), such combination appears frequently used in mUM patients. We here report our experience with nivolumab/ipilimumab in mUM. A retrospective cohort of 47 mUM patients, 24 men and 23 women, received nivolumab/ipilimumab between October 2019 and December 2021, mostly first line (94%). Two regimens were used: nivolumab 1 mg/kg + ipilimumab 3 mg/kg (nivo1ipi3, 49% of patients) and nivolumab 3 mg/kg + ipilimumab 1 mg/kg (nivo3ipi1, 51% of patients). Median follow-up was 37 and 88 weeks in nivo3ipi1 and nivo1ipi3 cohorts, respectively. We observed partial response in two patients (4%) and stable disease in 14 patients (30%), with no significant difference between the two regimens. Median progression-free survival was 13.6 weeks and 11.9 weeks in the nivo1ipi3 and nivo3ipi1 cohorts, respectively (p = 0.49). Severe adverse events (grade 3 or 4) were observed in seven patients (15%) among which five treated with nivo1ipi3 (22%) and two treated with nivo3ipi1 (8%). These data suggest that nivolumab/ipilimumab combination does not improve clinical outcomes compared to other therapies but is more toxic. In the absence of controlled clinical trials, we would not recommend this combination as a standard treatment in all mUM patients but rather as an option. Patients for whom the benefit-risk ratio could justify the combination need to be defined.

MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients.

BACKGROUND: MBD4 mutations have been reported in uveal melanomas, acute myeloid leukemias, colorectal adenocarcinomas, gliomas, and spiradenocarcinomas and cause a hypermutated phenotype. Although metastatic uveal melanomas (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI. METHODS: Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients. RESULTS: Three hundred mUM patients were included. Median follow-up was 17.3 months. Ten patients with an objective response and 20 cases with stable disease for >12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (i.e., responder patients and stable disease) rate of 10%. Of the 131 tumors sequenced for MBD4, five (3.8%) were mutated. MBD4 mutation was associated with a better objective response rate as three out of five MBD4m versus 4% of MBD4 wild-type patients responded (p < 0.001). Of these five responders, three presented progressive disease at 2.8, 13.9, and 22.3 months. Median PFS was 4.0 months in MBD4 wild-type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median OS in MBD4def patients was unreached as compared to 16.6 months in MBD4pro (HR = 0.11; 95% CI: 0.02-0.86; log-rank p-test = 0.04; Fig. 2e). CONCLUSIONS: In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.

[Homologous recombination deficiency and PARP inhibitors in therapeutics]. / Défauts de la recombinaison homologue et inhibiteurs de PARP en thérapeutique.

PARP inhibitors are effective in different types of tumors such as ovarian, breast, prostate and pancreatic cancer. Many studies are in progress and may lead to prescription evolution. PARP inhibitors prescription is almost reserved to patients with a constitutional BRCA mutation or a somatic BRCA alteration or a tumor with a deficiency in homologous recombination. Nowadays, the diagnosis of homologous recombination deficit, HRD, is possible with the prescription of a myChoice CDx (Myriad) test. PARP inhibitors are studied in association with chemotherapy and targeted therapies but also with radiotherapy and with immune checkpoint inhibitors. Access to PARP inhibitors is challenged with the emergence of resistance mechanism. Various trials are now studying the possibility of reversing these resistance mechanisms.

Cabazitaxel activity in men with metastatic castration-resistant prostate cancer with and without DNA damage repair defects.

BACKGROUND: Cabazitaxel was shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after abiraterone/enzalutamine and docetaxel failure, though benefit by the presence of DNA damage repair (DDR) defects is unknown. With the advent of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in partially overlapping indications with cabazitaxel, we aimed to determine cabazitaxel activity in men with mCRPC according to their DDR status. METHODS: This is a retrospective multicenter study that enrolled patients with mCRPC treated with cabazitaxel who had undergone DDR tumour tissue profiling. Patients with at least one deleterious germline or somatic alterations were considered DDR positive (DDR+). Each DDR + patient has been matched with a DDR negative (DDR-) from the same institution who underwent the same test. An exploratory cohort of patients found to be DDR + by liquid biopsy was also included. Prostate specific antigen (PSA) decline≥50% (PSA50), PSA progression-free survival (PFS, PSA-PFS), radiographic PFS (rPFS), clinical PFS or radiographic PFS (c/rPFS) and OS were evaluated. RESULTS: Among 190 men (95 DDR+, 95 DDR-) with tissue sequencing, PSA50 was achieved with cabazitaxel in 29/92 (32%) and 33/92 (36%) in patients with DDR+ and DDR- (P = 0.64). The median rPFS was 5.33 months [95%CI 4.34-7.04] versus 5.75 months [95%CI 4.67-7.27] (P = 0.55). The median OS was 15.4 months [95%CI 12.16-26.6] and 11.5 months [95%CI 9.76-14.4] (P = 0.036), respectively. No PSA50 responses on cabazitaxel were observed in BRCA1/2 patients previously treated with PARPi (n = 10). Similar outcomes with cabazitaxel were observed in the liquid biopsy cohort (n = 63 DDR+). CONCLUSIONS: Our study suggests that cabazitaxel is active in patients with mCRPC regardless of their DDR status, although its activity in men pretreated with a PARPi may be lower.

Factors Associated With Being Overweight and Obesity in People Living With Human Immunodeficiency Virus on Antiretroviral Therapy: Socioclinical, Inflammation, and Metabolic Markers.

BACKGROUND: We investigated the association between socioclinical, inflammatory, and metabolic markers and weight gain in people with human immunodeficiency virus (HIV) on combination antiretroviral therapy (cART). METHODS: Individuals from the COPANA cohort of normal weight (body mass index [BMI], 18.5-24.9 [ calculated as weight in kilograms divided by height in meters squared) at cART initiation who achieved virological suppression (viral load, <50 copies/mL) and maintained it through 36 months of treatment were selected. Clinical, immunovirological, and socioeconomic data and inflammation (high-sensitivity C-reactive protein, CXCL10, CXCL8, interleukin 6, soluble tumor necrosis factor receptors 1 and 2, soluble CD14, and soluble CD16) and serum metabolic (glucose, insulin, lipid profile, adiponectin, and leptin) markers were assessed. Factors associated with becoming overweight (BMI, 25-29.9) or obese (BMI, ≥30) at 36 months were assessed using multivariate logistic regression models. RESULTS: After 36 months of cART, 32 of 158 people with HIV (20%) became overweight or obese (21% female; 65% born in France and 23% born in sub-Saharan Africa; median BMI at cART initiation, 22 [interquartile range, 21-23]). After adjustment, higher BMI, originating from sub-Saharan Africa, living in a couple, and higher soluble tumor necrosis factor receptor 2 and lower adiponectin concentrations at cART initiation were associated with becoming overweight or obese. CONCLUSION: Weight gain on cART is multifactorial. Special attention should be given to migrants from sub-Saharan Africa. Monocyte activation and adipocyte dysfunction at cART initiation affect weight regulation.

Adverse events of targeted therapies approved for women's cancers.

Breast cancer and gynecologic cancers affect >3 million women worldwide each year. With advances in precision medicine, a growing number of targeted therapies have been approved recently, and new therapeutic classes have emerged, including cell cycle inhibitors for hormone receptor positive breast cancer, antibody drug conjugate for human epidermal growth factor receptor 2 positive and triple negative breast cancer, and poly-ADP-ribose polymerase inhibitors for ovarian cancer. This article focuses first on the challenges for health care systems to address the specificities of each emerging targeted therapy and new issues raised by oral antitumor treatments, including individualization of prescriptions, drug-drug interaction assessment, pharmaceutical counseling, patient education, and outpatient management. Then, we provide an overview of the main adverse effects of targeted therapies approved for breast and gynecologic cancers, such as hematologic toxicity of cyclin-dependent kinase 4/6 inhibitors and poly-ADP-ribose polymerase inhibitors, metabolic disorders of phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin inhibitors, and cardiovascular toxicity of agents targeting human epidermal growth factor receptor 2.

Lack of evidence for CDK12 as an ovarian cancer predisposing gene.

CDK12 variants were investigated as a genetic susceptibility to ovarian cancer in a series of 416 unrelated and consecutive patients with ovarian carcinoma and who carry neither germline BRCA1 nor BRCA2 pathogenic variant. The presence of CDK12 variants was searched in germline DNA by massive parallel sequencing on pooled DNAs. The lack of detection of deleterious variants and the observed proportion of missense variants in the series of ovarian carcinoma patients as compared with all human populations strongly suggests that CDK12 is not an ovarian cancer predisposing gene.

Elevated risk of viral rebound on ART in migrants living in France: role of socioeconomic factors.

BACKGROUND: In Western countries, viral rebound on antiretroviral therapy (ART) appears to occur more frequently in migrants. We aimed to assess the respective roles of socioeconomic factors and migration on viral rebound in people living with HIV (PLHIV) in France. METHODS: We included PLHIV in France, enrolled from 2004 to 2008 in the French ANRS-COPANA cohort, who started a first ART and achieved undetectability (<50 copies/ml) within 1 year. Determinants of viral rebound were assessed using Cox models including geographical origin, HIV transmission group, and clinicobiological and sociodemographic data. RESULTS: Of 499 included individuals, 288 were born in France, 158 in sub-Saharan Africa (SSA) and 53 in another country. Kaplan-Meier probabilities of viral rebound-free survival were similar for men having sex with men (MSM) and heterosexuals born in France, and lower in migrants from SSA or other countries (P<0.001). The crude hazard ratio (HR) of viral rebound was 2.49 (95% CI, 1.59, 3.90) in migrants from SSA and 1.78 (0.94, 3.88) in migrants from other countries compared with MSM born in France. Educational level, financial difficulties and HIV status disclosure had the biggest impact on the difference between the crude and adjusted HRs for viral rebound in migrants. In multivariable analysis, viral rebound was no longer associated with geographical origin, but with protease inhibitor-containing ART, a VACS index ≥35 as a potential indicator of frailty, poor financial status (difficulties or debts) and non-disclosure to friend(s). CONCLUSIONS: Socioeconomic factors affect outcomes on ART, even in the context of free access to HIV care and treatment. Patient-centred strategies should be encouraged with the intervention of social workers to address basic needs and promote social support for more socially vulnerable individuals.

Anti-gp41 antibody levels reflect HIV viral suppression and cellular reservoir in long-term antiretroviral-treated trial participants.

BACKGROUND: A major challenge to HIV cure strategies is the quantification of persistent reactivation-prone virus in people living with HIV. OBJECTIVES: To determine whether anti-gp41 antibody levels correlate with viral suppression and HIV-1 DNA levels in patients on ART. METHODS: Participants with plasma HIV-1 RNA below 50 copies/mL for >12 months were included from three ANRS cohorts (COPANA, MONOI and APROCO). Antibody levels to gp41 were measured by a low-sensitivity enzyme-linked immunoassay. Correlations with patient and virus characteristics, plasma HIV-1 RNA load (standard and ultrasensitive tests) and cell-associated HIV-1 DNA were assessed. RESULTS: Median age was 41 years and 77.5% of the 683 participants were men. Median CD4+ T cell count was 582 cells/mm3 and median viral suppression duration was 6.6 years (IQR 2.0-9.5). The overall median anti-gp41 antibody titre was 1.3 (IQR 0.6-1.9); median HIV-1 DNA level was 2.6 (IQR 2.1-3.0) log10 copies/106 leucocytes; and HIV-1 RNA was undetectable in 56% of samples. A lower titre of anti-gp41 antibodies correlated with male gender, longer viral suppression and lower HIV-1 DNA burden. Sustained undetectable HIV-1 RNA was associated with lower anti-gp41 levels [median 1.1 (IQR 0.5-1.6) versus 1.4 (IQR 0.7-1.9), P = 0.009]. CONCLUSIONS: Anti-gp41 levels decreased with the duration of antiviral suppression on ART. Lower titres were associated with lower HIV-1 DNA levels and longer duration of viral suppression, reflecting minimal antigen stimulation. Anti-gp41 antibody titration may be a useful biomarker reflecting long-term HIV-1 suppression on ART.

Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC+ CD4+ cell levels: a surrogate marker candidate of HIV-induced intestinal damage.

INTRODUCTION: Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV-1 infection. METHODS: Biomarker discovery approaches were performed in four independent cohorts, covering HIV-1 primary and chronic infection in 496 naïve or cART-treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre- and post-infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non-human primate models, representing pathogenic (macaque) and non-pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4, RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV-infected macaques treated with IL-21. RESULTS: We showed that sDPP4 levels were strongly decreased in primary HIV-1 infection. Strikingly, sDPP4 levels in primary HIV-1 infection predicted time to AIDS. They were not increased by cART in chronic HIV-1 infection (median 36 months on cART). In the gut of SIV-infected non-human primates, DPP4 mRNA was higher in CD4+ than CD4- leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL-21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity. CONCLUSION: These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV-induced intestinal damage.

Postoperative complications after bowel endometriosis surgery by shaving, disc excision, or segmental resection: a three-arm comparative analysis of 364 consecutive cases.

OBJECTIVE: To assess the postoperative complications related to three surgical procedures used in colorectal endometriosis: rectal shaving, disc excision, and segmental resection. DESIGN: Retrospective comparative study using data prospectively recorded in the North-West Inter Regional Female Cohort for Patients with Endometriosis (CIRENDO) database. SETTING: University tertiary referral center. PATIENT(S): A total of 364 consecutive patients with deep endometriosis infiltrating the rectosigmoid, were stratified into three arms according to the technique used. INTERVENTION(S): All patients had a laparoscopic surgical procedure to treat bowel endometriosis: rectal shaving (145 patients), disc excision (80 patients), or segmental colorectal resection (139 patients). MAIN OUTCOME MEASURE(S): Postoperative complication rate was assessed using Clavien-Dindo classification. RESULT(S): Clavien 3b postoperative complications were recorded in 43 patients (11.8%), two thirds of whom were managed by segmental colorectal resection (P<.001). Fourteen cases of rectovaginal fistula (3.8%) were reported: three in the shaving arm (2.1%), three in the disc excision arm (3.7%), and eight in the segmental colorectal resection arm (5.8%) (P=.13). Twenty-four cases (6.6%) of pelvic abscess were recorded in patients free of fistula or leakage. One year after the surgery pregnancy rate (PRs) and delivery rate were comparable between patients with or without severe complications who intended to get pregnant. Three years postoperatively, the PR in infertile patients was 66.7%, with spontaneous conception in 50% of cases. CONCLUSION(S): Our data suggest that using a strategy prioritizing shaving, whenever it is possible, could be related to a reduction in severe complication rates. However, prudence is required before concluding that extensive disease should not be treated by segmental resection because of the risk of complications.

Exploitation of Precision Medicine Trials Data: Examples of Long Responders From the SHIVA01 Trial.

PURPOSE: Precision medicine trials constitute a precious source of molecular data with prospective clinical annotations allowing the exploration of patients' subpopulations according to specific clinical or biological questions. Using the SHIVA01-the first randomized trial comparing molecularly targeted therapy on the basis of tumor molecular profiling versus conventional chemotherapy in metastatic cancer patients who failed standard of care therapy-annotated database, we report cases of patients treated in the trial with targeted therapy who experienced an objective response or prolonged disease stabilization in light of patients' molecular alterations. PATIENTS AND METHODS: We selected all patients included in SHIVA01 treated with a molecularly targeted agent (MTA) who experienced an objective response or disease stabilization that lasted longer than 6 months according to Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Among the 170 patients who received MTAs in the SHIVA01 trial, 15 patients (9%) experienced an objective response (n = 3) or disease stabilization that lasted longer than 6 months (n = 12). The most frequent histologic subtypes were breast cancer (27%) and cervical cancer (20%). Six patients, including three patients with breast cancer, were treated with abiraterone on the basis of androgen receptor protein overexpression. Five patients were treated with everolimus on the basis of a PTEN heterozygous deletion with loss of protein expression, PIK3CA mutation, or both alterations. The remaining four patients were treated with tamoxifen, erlotinib, imatinib, and vemurafenib on the basis of progesterone receptor expression, EGFR amplification, KIT mutation, and BRAF mutation, respectively. TP53 mutations were absent in responder patients. CONCLUSION: Analysis of patients who experienced objective responses or disease stabilization that lasted longer than 6 months allowed the identification of potential biomarkers of sensitivity and resistance to MTAs.

Impact of protease inhibitors on circulating PCSK9 levels in HIV-infected antiretroviral-naive patients from an ongoing prospective cohort.

OBJECTIVE: The study aims to assess the association between proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of LDL cholesterol (LDL-C) homeostasis, and HIV-related dyslipidaemia in a cohort of HIV-positive (HIV+) patients under protease inhibitors. METHODS: Plasma PCSK9 levels were measured in 103 HIV+ patients before and after initiating protease inhibitor-based antiretroviral therapy (ART), and in 90 HIV-negative controls matched for age and sex. PCSK9 was measured by ELISA. HIV+ patients who were not virologically suppressed at follow-up or were on lipid-lowering therapy were excluded. RESULTS: In HIV+ (median age 36 years; 77.7% men), PCSK9 levels did not increase after protease inhibitor exposure (median 14 months) (279.5 ng/ml before, 289.6 ng/ml after; P = 0.49) and were significantly elevated versus controls at all timepoints (adjusted P value before and after: <0.05). After protease inhibitor initiation, total cholesterol, LDL-C and HDL cholesterol levels increased, but LDL-C remained lower versus controls. At baseline, PCSK9 levels were positively associated with immunodeficiency and the severity of HIV disease [HIV-1 viral load (P = 0.01), CD4 T-cell count <200/µl, P = 0.002], stage C HIV disease (P = 0.0002). In protease inhibitor-treated patients, PCSK9 levels were no longer associated with HIV-related factors but with total cholesterol (P = 0.0006), LDL-C (P = 0.01), HDL cholesterol (P = 0.01), triglycerides (P = 0.05) and glycaemia (P = 0.006). CONCLUSION: PSCK9 levels are elevated in HIV+ patients. In ART-naive patients, the relationship between PCSK9 levels and infection severity suggests an effect of HIV disease. After initiating protease inhibitor-containing ART in virologically suppressed patients, PCSK9 levels were associated with dyslipidaemia similar to controls.

[What biomarkers for the future? The point of view of the residents in oncology after the ESMO 2016 Congress]. / Quels biomarqueurs d'avenir ? Le point de vue des internes en oncologie à l'issue du congrès de l'ESMO 2016.

Since the advent of the HER2 biomarker allowing access to treatment with trastuzumab, we observe an explosion in research for biomarkers, in which the economic pressure linked to the costs of developing new products must not be overlooked, in order to better select the molecules to be developed and the patients who can benefit from them. Personalized medicine takes a little more space each year in the overall care of our patients and the search for specific indicators, has become unavoidable. Rapid identification of oncogenic changes, their therapeutic targeting and the anticipation of resistance or toxicity mechanisms is a challenge. From blood markers, proteins to tumor genomic profiling and new markers in medical imaging, clinicians, researchers, and patients all are looking for the Holy Grail. This article synthetizes oncology resident's reflexions during the ESMO congress which took place in Copenhagen from 7 to 11 October 2016. The aim was to select the most relevant or promising results for future clinical practice.

Influence of adjuvant chemotherapy on anti-Müllerian hormone in women below 35 years treated for early breast cancer.

The impact of chemotherapy on fertility appears to be of essential importance for the youngest cancer survivors. The aim of this study was to assess plasma anti-Mullërian hormone (AMH) evolution, using an automated sensitive AMH immunoassay in women younger than 35 years old before and after treatment with adjuvant chemotherapy for early breast cancer. We selected 54 women aged less than 35 years old, at the time of breast cancer diagnosis, who received chemotherapy between 2008 and 2014, and with plasma samples collected from the diagnosis, to 1 year, 3 years and 5 years post-diagnosis. The median AMH decreased markedly in the year after the diagnosis compared with the pretreatment values (P < 0.0001), and slightly increased 2 years later (P = 0.007, comparing 1-year and 3-years post-diagnosis concentrations), without any additional AMH recovery 5 years after diagnosis. This recovery did not reach age-dependent AMH expected values (P < 0.0001, comparing AMH measured values to AMH expected values). Addition of taxanes to an anthracyclines + alkylating-based regimen was associated with a worse AMH decrease (P = 0.007). Ovarian tissue cryopreservation before treatment did not influence the AMH recovery. These results highlight the necessity of fertility counselling before treatment, especially in women wanting children.

Sub-Saharan African migrants have slower initial CD4+ cell recovery after combined antiretroviral treatment initiation than French natives.

OBJECTIVE: Poorer immunologic responses to combined antiretroviral treatment (cART) have been reported among sub-Saharan African (SSA) migrants than among native Europeans. We studied whether differences in CD4 cell recovery between French natives and SSA migrants starting first-line cART could be explained by differences in socioeconomic conditions, inflammatory marker levels, and other established determinants. METHODS: We compared 319 French natives and 175 SSA migrants (ANRS-COPANA cohort). Clinical, biological, and socioeconomic data (education, employment, income, and cohabiting partnership) were recorded at regular visits. A piecewise linear mixed-effects model was used to analyze CD4 cell count kinetics on cART. RESULTS: Compared with French natives, SSA migrants were more frequently women, younger, less educated, living in more adverse conditions, and had more frequent symptoms of depression. The rate of CD4 cell recovery during the first 4 months on cART was significantly slower in SSA migrants, despite a similar virologic response, but did not differ significantly thereafter. The mean CD4 cell count rose from 251 cells/µl at baseline to 508 cells/µl at 36 months in migrants, and from 308 to 623 cells/µl in natives (additional mean gain of 58 cells/µl in natives). The difference persisted after adjustment for clinical, updated socioeconomic, and living conditions (-0.40√CD4 cells/month, P = 0.04); 25-hydroxyvitamin D, monocyte chemoattractant protein-1 and soluble tumor necrosis factor receptor 1 (sTNFR1) levels were lower in SSA migrants, but only sTNFR1 contributed to the difference in CD4 slope. CONCLUSION: Initial CD4 cell recovery on cART was slower among SSA migrants than among French natives. This difference was not explained by established clinical and biological determinants or by socioeconomic status.

Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset.

Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI) were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establishment of viral reservoirs. We analyzed data from four cohorts of HIV+ patients, allowing us to study IP-10 levels before infection (Amsterdam cohort), as well as during controlled and uncontrolled viremia (ANRS cohorts). We also addressed IP-10 expression levels with regards to lymphoid tissues (LT) and blood viral reservoirs in patients and non-human primates. Pre-existing elevated IP-10 levels but not sCD63 associated with rapid CD4 T-cell loss upon HIV-1 infection. During PHI, IP-10 levels and to a lesser level IL-18 correlated with cell-associated HIV DNA, while 26 other inflammatory soluble markers did not. IP-10 levels tended to differ between HIV controllers with detectable and undetectable viremia. IP-10 was increased in SIV-exposed aviremic macaques with detectable SIV DNA in tissues. IP-10 mRNA was produced at higher levels in the small intestine than in colon or rectum. Jejunal IP-10+ cells corresponded to numerous small and round CD68neg cells as well as to macrophages. Blood IP-10 response negatively correlated with RORC (Th17 marker) gene expression in the small intestine. CXCR3 expression was higher on memory CD4+ T cells than any other immune cells. CD4 T cells from chronically infected animals expressed extremely high levels of intra-cellular CXCR3 suggesting internalization after ligand recognition. Elevated systemic IP-10 levels before infection associated with rapid disease progression. Systemic IP-10 during PHI correlated with HIV DNA. IP-10 production was regionalized in the intestine during early SIV infection and CD68+ and CD68neg haematopoietic cells in the small intestine appeared to be the major source of IP-10.

Late Antiretroviral Therapy (ART) Initiation Is Associated with Long-Term Persistence of Systemic Inflammation and Metabolic Abnormalities.

OBJECTIVES: HIV-induced immunodeficiency is associated with metabolic abnormalities and systemic inflammation. We investigated the effect of antiretroviral therapy (ART) on restoration of insulin sensitivity, markers of immune activation and inflammation. METHODS: Immunological, metabolic and inflammatory status was assessed at antiretroviral therapy initiation and three years later in 208 patients from the ANRS-COPANA cohort. Patients were compared according to their pre-ART CD4+ cell count (group 1: ≤ 200/mm3, n = 66 vs. group 2: > 200/mm3, n = 142). RESULTS: Median CD4+ cell count increased in both groups after 3 years of successful ART but remained significantly lower in group 1 than in group 2 (404 vs 572 cells/mm3). Triglyceride and insulin levels were higher or tended to be higher in group 1 than in group 2 at ART initiation (median: 1.32 vs 0.97 mmol/l, p = 0.04 and 7.6 vs 6.8 IU, p = 0.09, respectively) and remained higher after three years of ART (1.42 vs 1.16 mmol/L, p = 0.0009 and 8.9 vs 7.2 IU, p = 0.01). After adjustment for individual characteristics and antiretroviral therapy regimens (protease inhibitor (PI), zidovudine), insulin levels remained significantly higher in patients with low baseline CD4+ cell count. Baseline IL-6, sCD14 and sTNFR2 levels were higher in group 1 than in group 2. Most biomarkers of immune activation/inflammation declined during ART, but IL-6 and hsCRP levels remained higher in patients with low baseline CD4+ cell count than in the other patients (median are respectively 1.4 vs 1.1 pg/ml, p = 0.03 and 2.1 vs 1.3 mg/ml, p = 0.07). CONCLUSION: After three years of successful ART, low pretreatment CD4+ T cell count remained associated with elevated insulin, triglyceride, IL-6 and hsCRP levels. These persistent metabolic and inflammatory abnormalities could contribute to an increased risk of cardiovascular and metabolic disease.