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

Pattern of mycobacterial antigen detection in leprosy Detecção de padrões antigênicos de micobactérias na hanseníase

Immunohistochemistry reaction (Peroxidase anti-peroxidase - PAP) was carried out on fifty-two skin biopsies from leprosy patients with the purpose to identify the antigenic pattern in mycobacteria and to study the sensitivity of this method. Five different patterns were found: bacillar, granular, vesicular, cytoplasmatic and deposits, classified according to the antigenic material characteristics. Deposits (thinely particulate material) appeared more frequently, confirming the immunohistochemistry sensitivity to detect small amounts of antigens even when this material is not detected by histochemical stainings.<br>Foi realizada reação imunohistoquímica (Peroxidase anti-peroxidase-PAP) em 52 biópsias de pele de pacientes com hanseníase com o objetivo de verificar quais os padrões antigênicos das micobactérias e estudar a sensibilidade deste método como auxílio diagnóstico da hanseníase. Foram encontrados cinco padrões diferentes, classificados como bacilar, granular, vesicular, citoplasmático e depósitos, de acordo com a característica do material antigênico. Os depósitos (material finamente particulado) apareceram com maior frequencia confirmando a sensibilidade da imunohistoquímica na detecção de pequenas quantidades de antígeno, cujo material não é mais visto por colorações histoquímicas usuais

Substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort.

INTRODUCTION: The patterns and reasons for antiretroviral therapy (ART) drug substitutions are poorly described in resource-limited settings. METHODS: Time to and reason for drug substitution were recorded in treatment-naive adults receiving ART in two primary care treatment programmes in Cape Town. The cumulative proportion of patients having therapy changed because of toxicity was described for each drug, and associations with these changes were explored in multivariate models. RESULTS: Analysis included 2,679 individuals followed for a median of 11 months. Median CD4+ T-cell count at baseline was 85 cells/microl. Mean weight was 59 kg, mean age was 32 years and 71% were women. All started non-nucleoside reverse transcriptase inhibitor-based ART (60% on efavrienz) and 75% started on stavudine (d4T). After 3 years, 75% remained in care on-site, of whom 72% remained on their initial regimen. Substitutions due to toxicity of nevirapine (8% by 3 years), efavirenz (2%) and zidovudine (8%) occurred early. Substitutions on d4T occurred in 21% of patients by 3 years, due to symptomatic hyperlactataemia (5%), lipodystrophy (9%) or peripheral neuropathy (6%), and continued to accumulate over time. Those at greatest risk of hyperlactataemia or lipodystrophy were women on ART > or =6 months, weighing > or =75 kg at baseline. DISCUSSION: A high proportion of adult patients are able to tolerate their initial ART regimen for up to 3 years. In most instances treatment-limiting toxicities occur early, but continue to accumulate over time in patients on d4T. Whilst awaiting other treatment options, the risks of known toxicities could be minimized through early identification of patients at the highest risk

Determinants of loss to follow-up in patients on antiretroviral treatment, South Africa, 2004–2012: a cohort study

BACKGROUND : The number of Human Immunodeficiency Virus (HIV) infected people eligible for initiation on antiretroviral Therapy (ART) is increasing. ART programmatic success requires that patients who are taking ART remain on treatment and are followed up regularly. This study investigated factors associated with being lost to follow-up, in a cohort of patients enrolled in a pharmacovigilance study in South Africa. METHODS : This was a retrospective observational cohort study performed at one of the Medunsa National Pharmacovigilance Centre’s (MNPC) ART sentinel surveillance sites. Loss to Follow-up (LTFU) was defined as “a patient who had been followed up at the sentinel site, who had not had contact with the health facility for 180 days or more since their last recorded expected date of return or if there were 180 days or more between the expected date of return and the next clinic visit”. RESULTS : Out of 595 patients, 65.5 % (n = 390) were female and 23.4 % (n = 139) were LTFU. The median time on ART before LTFU was 21.5 months (interquartile range: 12.9 – 34.7 months). The incidence rate of LTFU was 103 per 1000 person-years in the first year on ART and increased to 405 per 1000 person-years in the eighth year of taking ART. Factors associated with becoming LTFU included not having a committed partner (Adjusted Hazard Ratio (aHR): 2.9, 95 % Confidence Interval (CI):1.19-6.97, p = 0.019), being self-employed (aHR: 13.9, 95 % CI:2.81 - 69.06, p = 0.001), baseline CD4 count > 200 cells/ml (aHR: 3.8, 95 % CI: 1.85-7.85, p < 0.001), detectable last known Viral Load (VL) (aHR: 3.6, 95 % CI:1.98 - 6.52, p < 0.001) and a last known World Health Organisation clinical stage three or four (aHR: 2.0, 95 % CI:1.22-3.27, p = 0.006). Patients that previously had an ART adverse event had a lower risk (aHR: 0.6, 95 % CI: 0.38 - 0.99, p = 0.044) of becoming LTFU than those that had not. CONCLUSION : The incidence rate of LTFU increases with additional years on ART. Intensified measures to improve patient retention on ART must be prioritised with increasing patient time on ART and in patients that are at increased risk of becoming lost to follow-up.The University of Pretoria School of Health systems and Public Health and the South African Field Epidemiology and Laboratory training program.http://www.biomedcentral.com/bmchealthservresam201