Smoking and life expectancy among HIV-infected individuals on antiretroviral therapy in Europe and North America.

BACKGROUND: Cardiovascular disease and non-AIDS malignancies have become major causes of death among HIV-infected individuals. The relative impact of lifestyle and HIV-related factors are debated. METHODS: We estimated associations of smoking with mortality more than 1 year after antiretroviral therapy (ART) initiation among HIV-infected individuals enrolled in European and North American cohorts. IDUs were excluded. Causes of death were assigned using standardized procedures. We used abridged life tables to estimate life expectancies. Life-years lost to HIV were estimated by comparison with the French background population. RESULTS: Among 17 995 HIV-infected individuals followed for 79 760 person-years, the proportion of smokers was 60%. The mortality rate ratio (MRR) comparing smokers with nonsmokers was 1.94 [95% confidence interval (95% CI) 1.56-2.41]. The MRRs comparing current and previous smokers with never smokers were 1.70 (95% CI 1.23-2.34) and 0.92 (95% CI 0.64-1.34), respectively. Smokers had substantially higher mortality from cardiovascular disease, non-AIDS malignancies than nonsmokers [MRR 6.28 (95% CI 2.19-18.0) and 2.67 (95% CI 1.60-4.46), respectively]. Among 35-year-old HIV-infected men, the loss of life-years associated with smoking and HIV was 7.9 (95% CI 7.1-8.7) and 5.9 (95% CI 4.9-6.9), respectively. The life expectancy of virally suppressed, never-smokers was 43.5 years (95% CI 41.7-45.3), compared with 44.4 years among 35-year-old men in the background population. Excess MRRs/1000 person-years associated with smoking increased from 0.6 (95% CI -1.3 to 2.6) at age 35 to 43.6 (95% CI 37.9-49.3) at age at least 65 years. CONCLUSION: Well treated HIV-infected individuals may lose more life years through smoking than through HIV. Excess mortality associated with smoking increases markedly with age. Therefore, increases in smoking-related mortality can be expected as the treated HIV-infected population ages. Interventions for smoking cessation should be prioritized

CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE.

BACKGROUND: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. METHODS AND FINDINGS: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. CONCLUSIONS: Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl

Formulation Development and In Vitro Characterization of Oral Floating in Situ Gelling Liquid System of Losartan Potassium

The Losartan potassium oral In situ gel F1.F2.F3.F4.F5.F6.F7 and F8 was developed using gelling agents such as Gellan gum, Iota carrageenan and HPMC K4M. • Physical compatibility study showed that the drug and excipients are physically compatible with each other. • Chemical compatibility study was performed using FT-IR spectroscopy and its studies revealed that there was no change in major peaks, thus confirming no interaction between the drug and excipients. • Calibration curve of Losartan potassium was constructed in simulated gastric fluid of pH 1.2 and it obeys Beer Lambert’s law. • 8 formulations of Losartan potassium In situ gel was prepared using varying concentrations of different polymers such as Gellan gum, Iota carrageenan along with HPMC K4M as the release retardants. • The prepared formulations (F1- F8) were evaluated for physical appearance, pourability, pH, viscosity, In vitro gelation study, In vitro buoyancy study, density, gel strength, percentage water uptake, drug content and In vitro drug release. • All the formulations had good physical appearance. • All the formulations except F3 exhibited good gelling capacity. The gel that was formed dispersed rapidly in the formulation F3 containing only Iota carrageenan as the main polymer. • All the formulations showed floating lag time of less than 1 minute and duration of floating are greater than 12 hours. • All the formulation exhibited lower density than the density of gastric fluid (⁓ 1.004 gcmˉ3). • Formulations F7 and F8 showed higher gel strength when compared to the other formulations. • The percentage water uptake was higher for formulations F7 and F8 due to the presence of combination of polymers Gellan gum and Iota carrageenan. • The percentage drug content of all the formulations was in the range of 87.5 – 92.74 % indicating uniform distribution of drugs. • In vitro drug release study showed that only the formulations F7 and F8 released 98.24 % and 98.64 % of drug respectively at the end of 12 hours, while the other formulations showed more than 90 % of drug release even before the period of 12 hours. • The In vitro release kinetics study of the optimized formulation F8 showed that the formulation followed Zero order kinetics and Non- fickian diffusion mechanism. • The stability studies indicated that the optimized formulation F8 was stable and did not show any significant changes in the physical appearance, pH, gelling capacity, floating time, viscosity, drug content and In vitro drug release at the end of 3 months. The overall results indicate that the formulation of Losartan potassium as oral floating In situ gel provides controlled release of the drug. This may improve the patient compliance due to ease of administration and reduction in dosing frequency. Hence, the developed formulation can be used as an alternative to the conventional dosage form for the treatment of Hypertension in patients. FUTURE PLANS: ❖ Scale-up studies of the optimized formulation ❖ In vivo and In vitro- In vivo correlation studies ❖ To perform Bioequivalence studie

The HIV continuum of care in European Union countries in 2013: data and challenges

BACKGROUND: UNAIDS has set a 90-90-90 target to curb the HIV epidemic by 2020, but methods used to assess whether countries have reached this target are not standardised, hindering comparisons. METHODS: Through a collaboration formed by the European Centre for Disease Prevention and Control (ECDC) with European HIV cohorts and surveillance agencies, we constructed a standardised, four-stage continuum of HIV care for 11 European Union (EU) countries for 2013. Stages were defined as: 1) number of people living with HIV (PLHIV) in the country by end of 2013; 2) proportion of stage 1 ever diagnosed; 3) proportion of stage 2 ever initiated ART; and 4) proportion of stage 3 who became virally-suppressed (≤200 copies/mL). Case surveillance data were used primarily to derive stages 1 (using back-calculation models) and 2, and cohort data for stages 3 and 4. RESULTS: In 2013, 674,500 people in the 11 countries were estimated to be living with HIV, ranging from 5,500 to 153,400 in each country. Overall HIV prevalence was 0.22% (range 0.09%-0.36%). Overall proportions, of each previous stage, were 84% diagnosed, 84% on ART, and 85% virally-suppressed (60% of PLHIV). Two countries achieved ≥90% for all stages, and over half had reached ≥90% for at least one stage. CONCLUSIONS: EU countries are nearing the 90-90-90 target. Reducing the proportion undiagnosed remains the greatest barrier to achieving this target, suggesting further efforts are needed to improve HIV testing rates. Standardising methods to derive comparable continuums of care remains a challenge

Major Challenges in clinical management of TB/HIV coinfected patients in Eastern Europe compared with Western Europe and Latin America

Objectives: rates of TB/HIV coinfection and multi-drug resistant (MDR)-TB are increasing in Eastern Europe (EE). We aimed to study clinical characteristics, factors associated with MDR-TB and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients in EE, Western Europe (WE) and Latin America (LA). Design and methods: between January 1, 2011, and December 31, 2013, 1413 TB/HIV patients (62 clinics in 19 countries in EE, WE, Southern Europe (SE), and LA) were enrolled. Results: significant differences were observed between EE (N = 844), WE (N = 152), SE (N = 164), and LA (N = 253) in the proportion of patients with a definite TB diagnosis (47%, 71%, 72% and 40%, p<0.0001), MDR-TB (40%, 5%, 3% and 15%, p<0.0001), and use of combination antiretroviral therapy (cART) (17%, 40%, 44% and 35%, p<0.0001). Injecting drug use (adjusted OR (aOR) = 2.03 (95% CI 1.00-4.09), prior anti-TB treatment (3.42 (1.88-6.22)), and living in EE (7.19 (3.28-15.78)) were associated with MDR-TB. Among 585 patients with drug susceptibility test (DST) results, the empiric (i.e. without knowledge of the DST results) anti-TB treatment included ≥3 active drugs in 66% of participants in EE compared with 90-96% in other regions (p<0.0001). Conclusions: in EE, TB/HIV patients were less likely to receive a definite TB diagnosis, more likely to house MDR-TB and commonly received empiric anti-TB treatment with reduced activity. Improved management of TB/HIV patients in EE requires better access to TB diagnostics including DSTs, empiric anti-TB therapy directed at both susceptible and MDR-TB, and more widespread use of cART

Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies

BACKGROUND: Health care for people living with HIV has improved substantially in the past two decades. Robust estimates of how these improvements have affected prognosis and life expectancy are of utmost importance to patients, clinicians, and health-care planners. We examined changes in 3 year survival and life expectancy of patients starting combination antiretroviral therapy (ART) between 1996 and 2013. METHODS: We analysed data from 18 European and North American HIV-1 cohorts. Patients (aged ≥16 years) were eligible for this analysis if they had started ART with three or more drugs between 1996 and 2010 and had at least 3 years of potential follow-up. We estimated adjusted (for age, sex, AIDS, risk group, CD4 cell count, and HIV-1 RNA at start of ART) all-cause and cause-specific mortality hazard ratios (HRs) for the first year after ART initiation and the second and third years after ART initiation in four calendar periods (1996–99, 2000–03 [comparator], 2004–07, 2008–10). We estimated life expectancy by calendar period of initiation of ART. FINDINGS: 88 504 patients were included in our analyses, of whom 2106 died during the first year of ART and 2302 died during the second or third year of ART. Patients starting ART in 2008–10 had lower all-cause mortality in the first year after ART initiation than did patients starting ART in 2000–03 (adjusted HR 0·71, 95% CI 0·61–0·83). All-cause mortality in the second and third years after initiation of ART was also lower in patients who started ART in 2008–10 than in those who started in 2000–03 (0·57, 0·49–0·67); this decrease was not fully explained by viral load and CD4 cell count at 1 year. Rates of non-AIDS deaths were lower in patients who started ART in 2008–10 (vs 2000–03) in the first year (0·48, 0·34–0·67) and second and third years (0·29, 0·21–0·40) after initiation of ART. Between 1996 and 2010, life expectancy in 20-year-old patients starting ART increased by about 9 years in women and 10 years in men. INTERPRETATION: Even in the late ART era, survival during the first 3 years of ART continues to improve, which probably reflects transition to less toxic antiretroviral drugs, improved adherence, prophylactic measures, and management of comorbidity. Prognostic models and life expectancy estimates should be updated to account for these improvements

The strengths and difficulties questionnaire as a predictor of parent-reported diagnosis of autism spectrum disorder and attention deficit hyperactivity disorder

notes: PMCID: PMC3848967This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The Strengths and Difficulties Questionnaire (SDQ) is widely used as an international standardised instrument measuring child behaviour. The primary aim of our study was to examine whether behavioral symptoms measured by SDQ were elevated among children with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) relative to the rest of the population, and to examine the predictive value of the SDQ for outcome of parent-reported clinical diagnosis of ASD/ADHD. A secondary aim was to examine the extent of overlap in symptoms between children diagnosed with these two disorders, as measured by the SDQ subscales. A cross-sectional secondary analysis of data from the Millennium Birth Cohort (n = 19,519), was conducted. Data were weighted to be representative of the UK population as a whole. ADHD or ASD identified by a medical doctor or health professional were reported by parents in 2008 and this was the case definition of diagnosis; (ADHD n = 173, ASD n = 209, excluding twins and triplets). Study children's ages ranged from 6.3-8.2 years; (mean 7.2 years). Logistic regression was used to examine the association between the parent-reported clinical diagnosis of ASD/ADHD and teacher and parent-reported SDQ subscales. All SDQ subscales were strongly associated with both ASD and ADHD. There was substantial co-occurrence of behavioral difficulties between children diagnosed with ASD and those diagnosed with ADHD. After adjustment for other subscales, the final model for ADHD, contained hyperactivity/inattention and impact symptoms only and had a sensitivity of 91% and specificity of 90%; (AUC) = 0.94 (95% CI, 0.90-0.97). The final model for ASD was composed of all subscales except the 'peer problems' scales, indicating of the complexity of behavioural difficulties that may accompany ASD. A threshold of 0.03 produced model sensitivity and specificity of 79% and 93% respectively; AUC = 0.90 (95% CI, 0.86-0.95). The results support changes to DSM-5 removing exclusivity clauses.ESRCNational Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsul

Risk Factors and Outcomes for Late Presentation for HIV-Positive Persons in Europe: Results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE).

Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality

Misdiagnosis and clinical significance of non-tuberculous mycobacteria in Western Kenya in the era of human immunodeficiency virus epidemic

Objectives: To determine and document the role of non-tuberculous mycobacteria (NTM) in TB-like disease morbidity and demonstrate the confusion they cause in the diagnosis of TB in western Kenya.Design: A cross-sectional study.Setting: One provincial and nine District hospitals in western Kenya.Subjects: Tuberculosis suspects.Interventions: Sputa from 872 tuberculosis suspects underwent microscopy and culture on solid and liquid media. The growth was identified using the Hain’s GenoType® Mycobacterium CM and GenoType® Mycobacterium AS kits. Consenting clients were screened for HIV infection using Trinity Biotech Uni-GoldTM test and positive cases were confirmed with the enzyme linked immunosorbent assay. A questionnaire was used to obtain demographic data.Main outcome measures: ZN smear positivity / negativity; Culture positivity or negativity; Mycobacterium species isolates (tuberculous or non-tuberculous); HIV status.                                                      Results: Sputa from 39.1% (341/872) of the participants were ZN smear positive, of these 53.1% (181/341) were culture positive. Only 3.8% (20/531) of the ZN smear negatives were culture positive. In total 41.4% (361/872) participants were infected with mycobacteria, of which 44.3% (160/361) were culture negative and 55.7% (201/361) were culture positive. The culture positives yielded 92.5% M. tuberculosis complexand 7.5% NTM. The overall prevalence of the NTM disease was 1.72% (15/872).                                                                            Conclusion: A low prevalence of NT M pulmonary disease in western Kenya is reported in this study, but some the NTM disease cases could have been misdiagnosed as TB cases

Association Study of Common Genetic Variants and HIV- 1 Acquisition in 6,300 Infected Cases and 7,200 Controls

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception ofCCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size