Explore the vast range of titles available.

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.

Purpose The aim of this study was to quantify the contribution of FDG PET to the diagnostic assessment of fever of unknown origin (FUO), taking into account the diagnostic limitations resulting from the composite nature of this entity. Methods The PubMed/MEDLINE database was searched from 2000 to September 2015. Original articles fulfilling the following criteria were included: (1) FUO as the initial diagnosis, (2) no immunosuppressed or nosocomial condition, (3) final diagnosis not based on PET, (4) a follow-up period specified, (5) adult population, and (6) availability of adapted data for calculation of odds ratios (ORs). ORs were computed for each study and then pooled using a random effects model. Stratification-based sensitivity analyses were finally performed using the following prespecified criteria: (a) study design, (b) PET device, (c) geographic area, and (d) follow-up period. Results A meta-analysis of the 14 included studies showed that normal PET findings led to an increase in the absolute final diagnostic rate of 36 % abnormal PET findings to an increase of 83 %, corresponding to a pooled OR of 8.94 (95 % CI 4.18 – 19.12, Z  = 5.65; p  < 0.00001). The design of the studies influenced the results (OR 2.92, 95 % CI 1.00 – 8.53 for prospective studies; OR 18,57, 95 % CI 7.57 – 45.59 for retrospective studies; p  = 0.01), whereas devices (dedicated or hybrid), geographic area and follow-up period did not. Conclusion Abnormal PET findings are associated with a substantially increased final diagnostic rate in FUO. Consequently, FDG PET could be considered for inclusion in the first-line diagnostic work-up of FUO. Further randomized prospective studies with standardized FDG PET procedures are warranted to confirm this first-line position.

Background Adult-onset Still disease (AOSD) is a rare systemic inflammatory disorder. A few patients develop organ complications that can be life-threatening. Our objectives were to describe the disease course and phenotype of life-threatening AOSD, including response to therapy and long-term outcome. Methods A multicenter case series of intensive care medicine (ICU) patients with life-threatening AOSD and a systematic literature review. Results Twenty patients were included. ICU admission mostly occurred at disease onset (90%). Disease manifestations included fever (100%), sore throat (65%), skin rash (65%), and arthromyalgia (55%). Serum ferritin was markedly high (median: 29,110 ng/mL). Acute respiratory failure, shock and multiple organ failure occurred in 15 (75%), 10 (50%), and 7 (35%) cases, respectively. Hemophagocytosis was demonstrated in eight cases. Two patients died. Treatment delay was significant. All patients received corticosteroids. Response rate was 50%. As second-line, intravenous immunoglobulins were ineffective. Anakinra was highly effective . After ICU discharge, most patients required additional treatment . Literature analysis included 79 cases of AOSD with organ manifestations, which mainly included reactive hemophagocytic syndrome (42%), acute respiratory failure (34%), and cardiac complications (23%). Response rate to corticosteroids was 68%. Response rates to IVIgs, cyclosporin, and anakinra were 50%, 80%, and 100%, respectively. Conclusions AOSD should be recognized as a rare cause of sepsis mimic in patients with fever of unknown origin admitted to the ICU. The diagnosis relies on a few simple clinical clues. Early intensive treatment may be discussed. IVIgs should be abandoned. Long-term prognosis is favorable.

Background. Combined antiretroviral therapy (cART) initiation during primary human immunodeficiency virus (HIV) infection (PHI) yields a larger decrease in cell-associated HIV-DNA (CA-HIV-DNA) than initiation during the chronic phase. Our objective was to model the short and long-term decay of CA-HIV-DNA blood reservoir in patients initiating cART during PHI and to assess the impact of the timing of cART initiation on CA-HIV-DNA decay. Methods. We included patients enrolled during PHI in the Agence Nationale de Recherche sur le Sida PRIMO cohort, treated within the month following enrollment and achieving sustained virologic response. The decay of CA-HIV-DNA over time while on successful cART was modeled with a 3-slope linear mixed-effects model according to the delay between estimated date of infection and cART initiation. Results. Three hundred twenty-seven patients were included, accounting for 1305 CA-HIV-DNA quantifications. Median time between infection and cART initiation was 41 days (interquartile range, 33–54 days). Median follow-up under cART was 2.3 years (range, 0.4–16.6 years). The timing of cART initiation had significant impact on the first slope of decrease: The earlier cART was initiated after HIV infection, the faster CA-HIV-DNA level decreased during the first 8 months of cART: −0.171, −0.131, and −0.068 log10 copies/106 peripheral blood mononuclear cells (PBMCs) per month when cART was initiated 15 days, 1 month, and 3 months after infection, respectively (P<.0001). The predicted mean CA-HIV-DNA level achieved after 5 years of successful cART was 1.62 and 2.24 log10 copies/106 PBMCs when cART was initiated 15 days and 3 months after infection, respectively (P=.0006). Conclusions. This study provides strong arguments in favor of cART initiation at the earliest possible time point after HIV infection.

Additional investigations showed that she had a low bone density of the distal radius (Z score SD −3·0, normal score SD −2) and increased markers of bone formation: alkaline phosphatase was 271 IU/L (normal range 42–98), osteocalcin was 87 ng/mL (normal range 2–12). In patients with hypoparathyroidism refractory to conventional treatment, rhPTH (1–34) therapy can effectively control hypocalcaemia, but whether it is safe in the long term is unclear. Supplementary Material Supplementary video Recombinant human parathyroid hormone (1-34) and (1-84) therapy for hypocalcaemia: long term effects.

Despite huge advances in the fight against HIV concerning diagnosis, clinical efficacy of antiretroviral treatments (ART), patient survival and quality of life, there is still no cure. Recent developments in HIV cure research have opened the way for clinical trials which could lead to a temporary or definitive end to ART. However, ethical questions exist about related trial-participation risks. The main goal of the ANRS-APSEC survey was, using Q-methodology, to investigate the viewpoints of people living with HIV (PLWH) and HIV healthcare providers (HHP) regarding motivations for and barriers to participation in HIV Cure-related clinical trials (HCRCT). Thirty-three statements were defined encompassing seven dimensions: treatment and follow-up; risks; benefits; patient-physician relationship; beliefs and attitudes; information; target population. Forty-one PLWH and 41 HHP from five French HIV services were asked to rank-order the statements. Five main viewpoints were elicited from \"the most motivated\" to \"the most reluctant\" vis-à-vis HCRCT participation. All placed importance on the wish to participate in HIV research. This result is in line with the HIV-specific culture of joint mobilization. For some viewpoints, the motivation to participate in/propose HCRCT was primarily conditioned by side-effects and/or by constraints, which overall were more accepted by PLWH than HHP. Some viewpoints placed particular importance on HCRCT recruitment strategies. Finally, some expressed a high acceptance of risks and constraints but emphasized the need for information. HIV cure research clinical trials (HCRCT) constitute a risky yet unavoidable step towards the goal of finding a cure. To improve future HCRCT and informed consent designs, based on PLWH and HHP preferences and expectations, we need greater knowledge about how these populations perceive the risks and the benefits of HCRCT. Our results confirmed the importance of careful, studied HCRCT design, management and communication, to ensure PLWH and HHP acceptability and convergence of their expectations.

Objectives Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder. Diagnosing AOSD can be challenging, as disease presentation and clinical course are highly heterogeneous. For unclear reasons, a few patients develop life-threatening complications. Our objective was to determine whether these cases resulted from therapeutic delay or could represent a peculiar AOSD subset. Methods We conducted a multicentre retrospective study of 20 AOSD patients with organ failure requiring intensive care unit admission and 41 control AOSD patients without organ failure. Clinico-biological data at hospital admission were explored using supervised analyses and unsupervised dimension reduction analysis (factor analysis of mixed data, FAMD). Results Disease duration before admission was shorter in patients with life-threatening AOSD (median, 10 vs 20 days, p = 0.007). Disease duration before AOSD therapy initiation also tended to be shorter (median, 24 vs 32 days, p = 0.068). Despite this shorter disease duration, FAMD, hierarchical clustering and univariate analyses showed that these patients exhibited distinctive characteristics at first presentation, including younger age; higher frequency of splenomegaly, liver, cardiac and/or lung involvement; less frequent arthralgia; and higher ferritin level. In multivariate analysis, 3 parameters predicted life-threatening complications: lack of arthralgia, younger age and shorter time between fever onset and hospitalisation. Conclusion This study suggests that life-threatening complications of AOSD occur very early, in a peculiar subset, which we propose to name catastrophic adult-onset Still’s disease (CAOSD). Its exact burden may be underestimated and remains to be clarified through large multicentre cohorts. Further studies are needed to identify red flags and define the optimal therapeutic strategy.

Introduction In a context of declining condom use and high sexually transmitted infection (STI) incidence, the diffusion of “treatment as prevention” (Tasp) and more recently pre‐exposure prophylaxis (PrEP) may have changed the sexual behaviour of newly diagnosed men who have sex with men (MSM) with HIV. Methods Six hundred and nine MSM were enrolled and followed annually between 2014 and 2021 in the ANRS PRIMO Cohort (ClinicalTrials.gov:NCT03148964) from the time of HIV seroconversion. We studied changes over calendar time in sexual behaviour before and after HIV diagnosis. Factors associated with inconsistent condom use (ICU) after HIV diagnosis, PrEP use by partner(s) and bacterial STI acquisition were studied in random‐effects models. Results In the 6 months preceding HIV diagnosis, the number of sexual partners decreased from a median of 10 (IQR: 4−19) in 2014 to 6 (3−11) in 2021. After HIV diagnosis, ICU increased from 57.1% (16/28) of visits in 2014 up to 84.2% (229/272) in 2020−2021. Up to 25% (63/229) of MSM with HIV in recent years reported the use of PrEP by their partner(s) as the reason for ICU; these MSM were less frequently in a stable relationship, had a higher number of sexual partners and higher education level than those who did not report the use of PrEP by their partner(s). STI incidence after HIV diagnosis increased between 2014 and 2016 and remained high afterwards. STI risk was no longer associated with PrEP use by partners after adjustment for the number of partners and calendar period. ICU, age below 35 years, not being in a stable relationship, higher number of sexual partners were independently associated with an increased risk of STI. Conclusions Implementation of TasP and more recently PrEP has led to major changes in the sexual behaviour of MSM with HIV. ICU has become overwhelmingly prevalent, PrEP use by the partner increasingly being the reported reason for ICU, behind TasP, which remains the main reason. Characteristics of MSM at the time of diagnosis of HIV have changed, with fewer number of sexual partners today than in 2014, which must lead to broaden the indications for PrEP prescription. STIs incidence remains high in MSM with HIV and requires improvements in screening and prevention methods such as pre‐ or post‐exposition antibiotics or vaccines.