Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

A qualitative study on the educational needs of young people with chronic conditions transitioning from pediatric to adult care

Maxime Morsa,1 Pierre Lombrail,1,2 Bernard Boudailliez,3,4 Cécile Godot,5 Vincent Jeantils,6 Rémi Gagnayre1 1Laboratory of Education and Health Practices (EA3412), Université Paris 13, Bobigny, Paris, France; 2Department of Public Health, Paris Seine St-Denis Hospital, AP-HP, Paris, France; 3Pediatric Department, Amiens University Hospital Center, Amiens, France; 4Medicine Faculty, University of Picardie Jules Verne, Amiens, France; 5Department of Endocrinology, Diabetology and Gynecology of Children and Adolescents, Necker Hospital, AP-HP, Paris, France; 6Infectious Diseases Unit, Jean Verdier Hospital, AP-HP, Paris, France Objectives: Although patient education is recommended to facilitate the transition from pediatric to adult care, a consensus has not been reached for a particular model. The specific skills needed for the transition to help in facilitating the life plans and health of young people are still poorly understood. This study explored the educational needs of young people with diverse chronic conditions during their transition from pediatric to adult care. Methods: Qualitative semi-structured interviews were conducted with 17 young people with chronic conditions. A thematic analysis was conducted to examine the data. Results: Five themes emerged from the data, identified through the following core topics: learning how to have a new role, learning how to adopt a new lifestyle, learning how to use a new health care service, maintaining a dual relationship with pediatric and adult care, and having experience sharing with peers. Conclusion: A shift in perspective takes place when the transition is examined through the words of young people themselves. To them, moving from pediatric to adult care is not viewed as the heart of the process. It is instead a change among other changes. In order to encourage a transition in which the needs of young people are met, educational measures could focus on the acquisition of broad skills, while also being person-centered. Keywords: transition, adolescence, chronic disease, pediatrics, patient educatio

Adjunctive corticosteroids for <it>Pneumocystis jiroveci </it>pneumonia in patients with HIV infection: a meta-analysis of randomised controlled trials

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to review the effects of adjunctive corticosteroids on overall mortality and the need for mechanical ventilation in HIV-infected patients with <it>Pneumocystis jiroveci </it>pneumonia (PCP) and substantial hypoxemia (arterial oxygen partial pressure <70 mmHg or alveolar-arterial gradient >35 mmHg on room air).</p> <p>Methods</p> <p>We conducted a systematic search of the literature for randomised trials published up to December 2004. Selected trials compared adjunctive corticosteroids with placebo or usual care in HIV-infected patients with PCP and reported mortality data. Two teams of reviewers independently evaluated the methodology and extracted data from each primary study.</p> <p>Results</p> <p>Six studies were included in the meta-analysis. Risk ratios for overall mortality for adjunctive corticosteroids were 0.54 (95% confidence interval [CI], 0.38–0.79) at 1 month and 0.67 (95% CI, 0.49–0.93) at 3–4 months of follow-up. Numbers needed to treat, to prevent 1 death, are 9 patients in a setting without highly active antiretroviral therapy (HAART) available and 22 patients with HAART available. Only the 3 largest trials provided data on the need for mechanical ventilation with a risk ratio of 0.37 (95% CI, 0.20–0.70) in favour of adjunctive corticosteroids.</p> <p>Conclusion</p> <p>The number and size of trials investigating adjunctive corticosteroids for HIV-infected patients with PCP is small, but our results suggest a beneficial effect for patients with substantial hypoxemia.</p

LEDIPASVIR/SOFOSBUVIR IN NS3/4A PROTEASE INHIBITOR-EXPERIENCED SUBJECTS WITH HCV GENOTYPE 1 AND HIV-COINFECTION FINAL RESULTS OF THE ANRS HC31 SOFTRIH STUDY

International audienceEASL International Liver Congress, APR 13-17, 2016, Barcelona, SPAI

Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study)

International audienceObjectives - Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis.Methods - We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes.Results - Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified.Conclusions - LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis

Protecting the Fetus Against HIV Infection: A Systematic Review of Placental Transfer of Antiretrovirals

BACKGROUND: Maternal-fetal transfer of antiretroviral drugs contributes to prevention of vertical transmission of HIV. OBJECTIVE: This systematic review discusses published studies containing data pertaining to the pharmacokinetics of placental transfer in humans, including paired cord and maternal plasma samples collected at the time of delivery as well as ex vivo placental perfusion models. METHODS: Articles pertaining to placental transfer of antiretrovirals were identified from PubMed, from references of included articles, and from U.S. Department of Health and Human Services Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission guidelines. Articles from non-human animal models or that had no original maternal-fetal transfer data were excluded. PRISMA guidelines were followed. RESULTS: A total of 103 published studies were identified. Data across studies appeared relatively consistent for the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleotide reverse transcriptase inhibitors (NNRTIs), with cord to maternal ratios approaching 1 for many of these agents. The protease inhibitors atazanavir and lopinavir exhibited consistent maternal-to-fetal transfer across studies, although the transfer may be influenced by variations in drug-binding proteins. The protease inhibitors indinavir, nelfinavir, and saquinavir exhibited unreliable placental transport, with cord blood concentrations that were frequently undetectable. Limited data, primarily from case reports, indicate that darunavir and raltegravir provide detectable placental transfer. CONCLUSION: These findings appear consistent with current guidelines of using two NRTIs plus an NNRTI, atazanavir/ritonavir, or lopinavir/ritonavir to maximize placental transfer as well as to optimally suppress maternal viral load. Darunavir/ritonavir and raltegravir may reasonably serve as second-line agents

HIV-1 subtype B-infected MSM may have driven the spread of transmitted resistant strains in France in 2007–12: impact on susceptibility to first-line strategies

International audienceBackground: Our study describes the prevalence of transmitted drug resistance (TDR) among 1318 French patients diagnosed at the time of primary HIV-1 infection (PHI) in 2007-12.Methods: HIV-1 resistance-associated mutations (RAMs) were characterized using both the 2009 WHO list of mutations and the French ANRS algorithm. A genotypic susceptibility score was estimated for each first-line recommended ART combination.Results: Patients were mainly MSM (72.6%). Non-B variants were identified in 33.7% of patients. The proportion of TDR was estimated as 11.7% (95% CI 10.0-13.5). The prevalences of PI-, NRTI-, first-generation NNRTI and etravirine/rilpivirine-associated RAMs were 2.5%, 5.2%, 3.9% and 3.2%, respectively. Single, dual and triple class resistance was found in 9.6%, 1.0% and 1.1% of cases, respectively. Additionally, 5/331 strains isolated in 201012 had integrase inhibitor (II)-related RAMs (isolated E157Q mutation in all cases). TDR was more common among MSM than in other groups (12.9% versus 8.6%, P = 0.034), and in case of B versus non-B subtype infections (13.6% versus 7.9%, P = 0.002). The proportions of fully active combinations were >= 99.2%, >= 97.3% and >= 95.3% in cases of PI-, II- and NNRTI-based regimens, respectively. In 2010-12, the proportion of fully active efavirenz-based ART was lower in cases of subtype B versus non-B infection (P = 0.021).Conclusions: Compared with our previous studies, the proportion of NRTI- and first-generation NNRTI-related TDR has continued to decline in French seroconverters. However, subtype B-infected MSM could drive the spread of resistant HIV strains. Finally, we suggest preferring PI- or II- to NNRTI-based combinations to treat PHI patients