Renal Impairment and Cardiovascular Disease in HIV-positive Individuals; The D:A:D Study

BACKGROUND: While the association between renal impairment and cardiovascular disease (CVD) is well established in the general population, the association remains poorly understood in HIV-positive individuals. METHODS: Individuals with >2 estimated glomerular filtration rate (eGFRs) after 1/2/2004 were followed until CVD, death, last visit plus six months or 1/2/2015. CVD was defined as centrally validated myocardial infarction, stroke, invasive cardiovascular procedures or sudden cardiac death. RESULTS: During 8.0 years median follow-up (Interquartile range 5.4-8.9) 1,357 of 35,357 developed CVD (incidence 5.2/1000 person-years [95%confidence interval, CI [5.0-5.5]). Confirmed baseline eGFR and CVD were closely related with 1.8% [95%CI 1.6-2.0%] estimated to develop CVD at five years at eGFR>90 ml/min/1.73m(2), increasing to 21.1% [95%CI 6.6-35.6%] at eGFR<30 ml/min/1.73m(2) The strong univariate relationship between low current eGFR and CVD was primarily explained by increasing age in adjusted analyses, although all eGFRs<80 ml/min/1.73m(2) remained associated with 30-40% increased CVD rates and particular high rates at eGFR<30 ml/min/1.73m(2) (3.08 [95%CI 2.04-4.65]). CONCLUSIONS: Among HIV-positive individuals in a large contemporary cohort a strong relation between confirmed impaired eGFR and CVD was observed. This finding highlights the need for renal preventive measures and intensified monitoring for emerging CVD, in particular in older individuals with continuously low eGFR

Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

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

Can Linear Regression Modeling Help Clinicians in the Interpretation of Genotypic Resistance Data? An Application to Derive a Lopinavir-Score

The question of whether a score for a specific antiretroviral (e.g. lopinavir/r in this analysis) that improves prediction of viral load response given by existing expert-based interpretation systems (IS) could be derived from analyzing the correlation between genotypic data and virological response using statistical methods remains largely unanswered.We used the data of the patients from the UK Collaborative HIV Cohort (UK CHIC) Study for whom genotypic data were stored in the UK HIV Drug Resistance Database (UK HDRD) to construct a training/validation dataset of treatment change episodes (TCE). We used the average square error (ASE) on a 10-fold cross-validation and on a test dataset (the EuroSIDA TCE database) to compare the performance of a newly derived lopinavir/r score with that of the 3 most widely used expert-based interpretation rules (ANRS, HIVDB and Rega). Our analysis identified mutations V82A, I54V, K20I and I62V, which were associated with reduced viral response and mutations I15V and V91S which determined lopinavir/r hypersensitivity. All models performed equally well (ASE on test ranging between 1.1 and 1.3, p = 0.34).We fully explored the potential of linear regression to construct a simple predictive model for lopinavir/r-based TCE. Although, the performance of our proposed score was similar to that of already existing IS, previously unrecognized lopinavir/r-associated mutations were identified. The analysis illustrates an approach of validation of expert-based IS that could be used in the future for other antiretrovirals and in other settings outside HIV research

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

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 &gt; 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 (&gt;3 mo apart) eGFR ≤ 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts.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 &lt; 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0–4, 103 events) and high risk groups (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

Effect of Changes in Body Mass Index on the Risk of Cardiovascular Disease and Diabetes Mellitus in HIV-Positive Individuals: Results From the D:A:D Study

BACKGROUND: Weight gain is common among people with HIV once antiretroviral treatment (ART) is commenced. We assess the effect of changes in body mass index (BMI), from different baseline BMI levels, on the risk of cardiovascular disease (CVD) and diabetes mellitus (DM). METHODS: D:A:D participants receiving ART were followed from their first BMI measurement to the first of either CVD or DM event, or earliest of 1/2/2016 or 6 months after last follow-up. Participants were stratified according to their baseline BMI, and changes from baseline BMI were calculated for each participant. Poisson regression models were used to assess the effects of changes on BMI on CVD or DM events. RESULTS: There were 2,104 CVD and 1,583 DM events over 365,287 and 354,898 person years (rate: CVD 5.8/1000 (95% CI 5.5-6.0); DM 4.5/1000 (95% CI 4.2 - 4.7)). Participants were largely male (74%), baseline mean age of 40 years and median BMI of 23.0 (IQR: 21.0-25.3). Risk of CVD by change in BMI from baseline, stratified by baseline BMI strata showed little evidence of an increased risk of CVD with an increased BMI in any baseline BMI strata. An increase in BMI was associated with an increased risk of DM across all baseline BMI strata. CONCLUSIONS: While increases in BMI across all levels of baseline BMI were not associated with an increased risk of CVD, such changes were consistently associated with increased risk of DM. There was also some evidence of an increased risk of CVD with a decrease in BMI

Attitudes and behaviours of adolescents towards antibiotics and self-care for respiratory tract infections: a qualitative study.

BACKGROUND: To understand attitudes and behaviours of adolescents towards antibiotics, antimicrobial resistance and respiratory tract infections. DESIGN: Qualitative approach informed by the Theory of Planned Behaviour. Semi-structured interviews and focus groups were undertaken. We aimed to inform the development of an intervention in an international setting to improve antibiotic use among adolescents; therefore on completion of thematic analysis, findings were triangulated with qualitative data from similar studies in France, Saudi Arabia and Cyprus to elucidate differences in the behaviour change model and adaptation to diverse contexts. SETTING: 7 educational establishments from the south of England. PARTICIPANTS: 53 adolescents (16-18 years) participated in seven focus groups and 21 participated in interviews. RESULTS: Most participants had taken antibiotics and likened them to other common medications such as painkillers; they reported that their peers treat antibiotics like a 'cure-all' and that they themselves were not interested in antibiotics as a discussion topic. They demonstrated low knowledge of the difference between viral and bacterial infections.Participants self-cared for colds and flu but believed antibiotics are required to treat other RTIs such as tonsillitis, which they perceived as more 'serious'. Past history of taking antibiotics for RTIs instilled the belief that antibiotics were required for future RTIs. Those who characterised themselves as 'non-science students' were less informed about antibiotics and AMR. Most participants felt that AMR was irrelevant to them and their peers. Some 'non-science' students thought resistance was a property of the body, rather than bacteria. CONCLUSION: Addressing adolescents' misperceptions about antibiotics and the treatment of RTIs using a behaviour change intervention should help improve antibiotic awareness and may break the cycle of patient demand for antibiotics to treat RTIs amongst this group. Schools should consider educating all students in further education about antibiotic usage and AMR, not only those taking science

Increased Prevalence of Albuminuria in HIV-Infected Adults with Diabetes

HIV and type 2 diabetes are known risk factors for albuminuria, but no previous reports have characterized albuminuria in HIV-infected patients with diabetes.We performed a cross-sectional study including 73 HIV-infected adults with type 2 diabetes, 82 HIV-infected non-diabetics, and 61 diabetic control subjects without HIV. Serum creatinine >1.5 mg/dL was exclusionary. Albuminuria was defined as urinary albumin/creatinine ratio >30 mg/g.The prevalence of albuminuria was significantly increased among HIV-infected diabetics (34% vs. 13% of HIV non-diabetic vs. 16% diabetic control, p = 0.005). HIV status and diabetes remained significant predictors of albuminuria after adjusting for age, race, BMI, and blood pressure. Albumin/creatinine ratio correlated significantly with HIV viral load (r = 0.28, p = 0.0005) and HIV-infected subjects with albuminuria had significantly greater cumulative exposure to abacavir (p = 0.01). In an adjusted multivariate regression analysis of HIV-infected subjects, the diagnosis of diabetes (p = 0.003), higher HIV viral load (p = 0.03) and cumulative exposure to abacavir (p = 0.0009) were significant independent predictors of albuminuria.HIV and diabetes appear to have additive effects on albuminuria which is also independently associated with increased exposure to abacavir and HIV viral load. Future research on the persistence, progression and management of albuminuria in this unique at-risk population is needed

Predictors of estimated glomerular filtration rate progression, stabilization or improvement after chronic renal impairment in HIV-positive individuals

OBJECTIVES: The objectives of this analysis were to investigate predictors of progression, stabilisation or improvement in eGFR after development of chronic renal impairment (CRI) in HIV-positive individuals. DESIGN: Prospective observational study. METHODS: D:A:D study participants progressing to CRI defined as confirmed, ≥3 months apart, eGFR≤70 mL/min/1.73m were included in the analysis. The median of all eGFRs measured 24-36 months post-CRI was compared to the median eGFR defining CRI, and changes were grouped into: improvement (>+10 mL/min/1.73m), stabilisation (-10 to +10 mL/min/1.73m) and progression (12 months (1.17 [0.87-1.57]) had similar eGFR outcomes as those unexposed to these ARVs. Older age, hypertension, later date of CRI and diabetes were associated with worse eGFR outcomes. CONCLUSION: Current TDF and ATV/r use after a diagnosis of CRI was associated with worse eGFR outcomes. In contrast, TDF and ATV/r discontinuation lead to similar longer-term eGFR outcomes as in those unexposed suggesting these drug- associated eGFR declines may be halted or reversed after their cessation