Incidence of hypertension in people with HIV who are treated with integrase inhibitors versus other antiretroviral regimens in the RESPOND cohort consortium.

OBJECTIVE: To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts. METHODS: Eligible people with HIV were aged ≥18 years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ≥140 mmHg and/or diastolic BP ≥90 mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART naïve or experienced at baseline. RESULTS: Overall, 4606 people living with HIV were eligible (INSTIs 3164, NNRTIs 807, PIs 635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113-130) mmHg, 78 (70-82) mmHg, and 43 (34-50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0-2.7] years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9-134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47-2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89-1.29). The results were similar when the analysis was stratified by ART status at baseline. CONCLUSION: Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-naïve and ART-experienced participants within RESPOND.

Risk for Non-AIDS-Defining and AIDS-Defining Cancer of Early Versus Delayed Initiation of Antiretroviral Therapy : A Multinational Prospective Cohort Study.

BACKGROUND: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 109 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear. OBJECTIVE: To estimate the long-term risk difference for cancer with the immediate ART strategy. DESIGN: Multinational prospective cohort study. SETTING: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States. PARTICIPANTS: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016). MEASUREMENTS: The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts <350 and <500 × 109 cells/L) ART initiation strategies. RESULTS: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 109 cells/L and less than 350 × 109 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer. LIMITATION: Potential residual confounding due to observational study design. CONCLUSION: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer. PRIMARY FUNDING SOURCE: Highly Active Antiretroviral Therapy Oversight Committee.

The Impact of Immunosuppression on Chronic Kidney Disease in People Living With Human Immunodeficiency Virus: The D:A:D Study.

BACKGROUND: Relations between different measures of human immunodeficiency virus-related immunosuppression and chronic kidney disease (CKD) remain unknown. METHODS: Immunosuppression measures included baseline, current, time-lagged and nadir CD4, years and percentage of follow-up (%FU) with CD4 ≤200 cells/µL, and CD4 recovery. CKD was defined as confirmed estimated glomerular filtration rate <60 mL/minute/1.73 m2. RESULTS: Of 33 791 persons, 2226 developed CKD. Univariably, all immunosuppression measures predicted CKD. Multivariably, the strongest predictor was %FU CD4 ≤200 cells/µL (0 vs >25%; incidence rate ratio [IRR], 0.77 [95% confidence interval [CI], .68-.88]), with highest effect in those at low D:A:D CKD risk (IRR, 0.45 [95% CI, .24-.80]) vs 0.80 [95% CI, .70-.93]). CONCLUSIONS: Longer immunosuppression duration most strongly predicts CKD and affects persons at low CKD risk more.

Use of Contemporary Protease Inhibitors and Risk of Incident Chronic Kidney Disease in Persons With Human Immunodeficiency Virus: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study.

BACKGROUND: It is unclear whether use of contemporary protease inhibitors pose a similar risk of chronic kidney disease (CKD) as use of older protease inhibitors. METHODS: Participants in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study were followed up until the earliest occurrence of CKD, the last visit plus 6 months, or 1 February 2016. Adjusted Poisson regression was used to assess associations between CKD and the use of ritonavir-boosted atazanavir (ATV/r) or ritonavir-boosted darunavir (DRV/r). RESULTS: The incidence of CKD (10.0/1000 person-years of follow-up; 95% confidence interval, 9.5-10.4/1000 person-years of follow-up) increased gradually with increasing exposure to ATV/r, but the relation was less clear for DRV/r. After adjustment, only exposure to ATV/r (adjusted incidence rate ratio, 1.4; 95% confidence interval, 1.2-1.6), but not exposure to DRV/r (1.0; .8-1.3), remained significantly associated with CKD. CONCLUSION: While DRV/r use was not significantly associated with CKD an increasing incidence with longer ATV/r use was confirmed.

Cessation of Cigarette Smoking and the Impact on Cancer Incidence in Human Immunodeficiency Virus-infected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study.

Background: Cancers are a major source of morbidity and mortality for human immunodeficiency virus (HIV)-infected persons, but the clinical benefits of smoking cessation are unknown. Methods: Participants were followed from 1 January 2004 until first cancer diagnosis, death, or 1 February 2016. Smoking status was defined as ex-smoker, current smoker, and never smoker. Adjusted incidence rate ratios (aIRRs) were calculated using Poisson regression, adjusting for demographic and clinical factors. Results: In total 35442 persons from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study contributed 309803 person-years of follow-up. At baseline, 49% were current smokers, 21% were ex-smokers, and 30% had never smoked. Incidence of all cancers combined (n = 2183) was highest <1 year after smoking cessation compared to never smokers (aIRR, 1.66 [95% confidence interval {CI}, 1.37-2.02]) and not significantly different from never smokers 1-1.9 years after cessation. Lung cancer incidence (n = 271) was elevated <1 year after cessation (aIRR, 19.08 [95% CI, 8.10-44.95]) and remained 8-fold higher 5 years after smoking cessation (aIRR, 8.69 [95% CI, 3.40-22.18]). Incidence of other smoking-related cancers (n = 622) was elevated in the first year after cessation (aIRR, 2.06 [95% CI, 1.42-2.99]) and declined to a level similar to nonsmokers thereafter. Conclusions: Lung cancer incidence in HIV-infected individuals remained elevated >5 years after smoking cessation. Deterring uptake of smoking and smoking cessation efforts should be prioritised to reduce future cancer risk.

Role of pre-stroke immunity in ischemic stroke mechanism among patients with HIV.

Individuals with HIV are at a higher risk of stroke compared to uninfected populations. The role of HIV-related immunosuppression in stroke mechanism is uncertain. Our aim is to test the hypothesis that stroke mechanisms among HIV+ individuals vary according to preceding CD4 counts. We carried out a retrospective chart review of inpatient admissions for ICD-9 defined ischemic events (TIA or stroke) in HIV+ individuals from 2002 to 2016 at a tertiary care center. Stroke mechanisms were ascertained based on radiographic and clinical presentation, and adjudicated by the treating team and confirmed separately by a vascular neurologist. Vascular risk factors, use of antiretroviral drugs (ARVs), nadir CD4 and current CD4 counts (cells/mm3) were captured to build logistic regressions and generalized linear models to calculate the odds ratios (OR) and beta estimates with their respective 95% confidence intervals. We found that among 115 cases (median age 52, 64% men), stroke mechanisms were 22% due to large artery atherosclerosis (LAA), 17% small artery disease, 16% infectious, 8% cardioembolic, 21% cryptogenic, and 16% other etiologies. The median nadir CD4-count was 153 (IQR 22-274), and 312 (IQR 88-518) at the time of stroke, and 53% were on ARVs. LAA was more common with longer HIV infection (OR 1.1 per year, 1.0-1.2) and nadir CD4 counts <200 (OR 6.7, 1.4-31.9). Stroke due to LAA was associated with higher CD4 count the year prior to stroke (B = 0.009, P = 0.06 for the interaction) independent of CD4 nadir <200 (B = 1.88, P = 0.035). We concluded that in this sample, LAA was the most frequent stroke mechanism among HIV+ individuals with nadir CD4 < 200 but higher CD4 counts near the time of stroke. Determining the association between pre-stroke immune status and stroke mechanisms may allow a targeted approach to stroke prevention.

Cardiovascular disease (CVD) and chronic kidney disease (CKD) event rates in HIV-positive persons at high predicted CVD and CKD risk: A prospective analysis of the D:A:D observational study.

BACKGROUND: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study has developed predictive risk scores for cardiovascular disease (CVD) and chronic kidney disease (CKD, defined as confirmed estimated glomerular filtration rate [eGFR] ≤ 60 ml/min/1.73 m2) events in HIV-positive people. We hypothesized that participants in D:A:D at high (>5%) predicted risk for both CVD and CKD would be at even greater risk for CVD and CKD events. METHODS AND FINDINGS: We included all participants with complete risk factor (covariate) data, baseline eGFR > 60 ml/min/1.73 m2, and a confirmed (>3 months apart) eGFR < 60 ml/min/1.73 m2 thereafter to calculate CVD and CKD risk scores. We calculated CVD and CKD event rates by predicted 5-year CVD and CKD risk groups (≤1%, >1%-5%, >5%) and fitted Poisson models to assess whether CVD and CKD risk group effects were multiplicative. A total of 27,215 participants contributed 202,034 person-years of follow-up: 74% male, median (IQR) age 42 (36, 49) years, median (IQR) baseline year of follow-up 2005 (2004, 2008). D:A:D risk equations predicted 3,560 (13.1%) participants at high CVD risk, 4,996 (18.4%) participants at high CKD risk, and 1,585 (5.8%) participants at both high CKD and high CVD risk. CVD and CKD event rates by predicted risk group were multiplicative. Participants at high CVD risk had a 5.63-fold (95% CI 4.47, 7.09, p < 0.001) increase in CKD events compared to those at low risk; participants at high CKD risk had a 1.31-fold (95% CI 1.09, 1.56, p = 0.005) increase in CVD events compared to those at low risk. Participants' CVD and CKD risk groups had multiplicative predictive effects, with no evidence of an interaction (p = 0.329 and p = 0.291 for CKD and CVD, respectively). The main study limitation is the difference in the ascertainment of the clinically defined CVD endpoints and the laboratory-defined CKD endpoints. CONCLUSIONS: We found that people at high predicted risk for both CVD and CKD have substantially greater risks for both CVD and CKD events compared with those at low predicted risk for both outcomes, and compared to those at high predicted risk for only CVD or CKD events. This suggests that CVD and CKD risk in HIV-positive persons should be assessed together. The results further encourage clinicians to prioritise addressing modifiable risks for CVD and CKD in HIV-positive people.

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 human immunodeficiency virus (HIV)-positive individuals. METHODS: Individuals with ≥2 estimated glomerular filtration rate (eGFR) measurements after 1 February 2004 were followed until CVD, death, last visit plus 6 months, or 1 February 2015. CVD was defined as the occurrence of centrally validated myocardial infarction, stroke, invasive cardiovascular procedures, or sudden cardiac death. RESULTS: During a median follow-up duration of 8.0 years (interquartile range, 5.4-8.9 years) 1357 of 35 357 individuals developed CVD (incidence rate, 5.2 cases/1000 person-years [95% confidence interval {CI}, 5.0-5.5]). Confirmed baseline eGFR and CVD were closely related with 1.8% of individuals (95% CI, 1.6%-2.0%) with an eGFR > 90 mL/minute/1.73 m(2) estimated to develop CVD at 5 years, increasing to 21.1% (95% CI, 6.6%-35.6%) among those with an eGFR ≤ 30 mL/minute/1.73 m(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/minute/1.73 m(2) remained associated with 30%-40% increased CVD rates, and particularly high CVD rates among individuals with an eGFR ≤ 30 mL/minute/1.73 m(2) (incidence rate ratio, 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, particularly in older individuals with continuously low eGFRs.

A review of paediatric tuberculosis in Denmark: 10-year trend, 2000-2009.

Paediatric tuberculosis (TB) is a key indicator for recent transmission and presents a reservoir for the disease. We describe trends in epidemiology, microbiological characteristics and treatment outcome in Denmark between 2000 and 2009. Data were retrieved from the national TB surveillance system and the International Reference Laboratory of Mycobacteriology. In total, 323 TB cases were reported in children aged <15 years, accounting for 7.6% of all notified cases in Denmark. The overall incidence rate of childhood TB declined from 4.1 per 100,000 to 1.9 per 100,000 in the study period. Immigrant children comprised 79.6% of all cases, with the highest incidence rate of 94.1 per 100,000 children in 2001. In contrast to immigrant children, the majority of Danish children were aged <5 years and had a known exposure to TB. Pulmonary TB was the commonest presentation. Only half of the cases were culture confirmed. We observed an overall decreasing trend in the child to adult notification ratio, but a slight increase in the ratio when calculated specifically for ethnic Danes. Childhood TB needs continuous attention with a special focus on risk groups. Emphasis on improving early TB case detection, contact tracing and further implementation of preventive treatment is necessary.

Trends in Cancer Incidence in Different Antiretroviral Treatment-Eras amongst People with HIV.

Despite cancer being a leading comorbidity amongst individuals with HIV, there are limited data assessing cancer trends across different antiretroviral therapy (ART)-eras. We calculated age-standardised cancer incidence rates (IRs) from 2006-2021 in two international cohort collaborations (D:A:D and RESPOND). Poisson regression was used to assess temporal trends, adjusted for potential confounders. Amongst 64,937 individuals (31% ART-naïve at baseline) and 490,376 total person-years of follow-up (PYFU), there were 3763 incident cancers (IR 7.7/1000 PYFU [95% CI 7.4, 7.9]): 950 AIDS-defining cancers (ADCs), 2813 non-ADCs, 1677 infection-related cancers, 1372 smoking-related cancers, and 719 BMI-related cancers (groups were not mutually exclusive). Age-standardised IRs for overall cancer remained fairly constant over time (8.22/1000 PYFU [7.52, 8.97] in 2006-2007, 7.54 [6.59, 8.59] in 2020-2021). The incidence of ADCs (3.23 [2.79, 3.72], 0.99 [0.67, 1.42]) and infection-related cancers (4.83 [4.2, 5.41], 2.43 [1.90, 3.05]) decreased over time, whilst the incidence of non-ADCs (4.99 [4.44, 5.58], 6.55 [5.67, 7.53]), smoking-related cancers (2.38 [2.01, 2.79], 3.25 [2.63-3.96]), and BMI-related cancers (1.07 [0.83, 1.37], 1.88 [1.42, 2.44]) increased. Trends were similar after adjusting for demographics, comorbidities, HIV-related factors, and ART use. These results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-, and BMI-related cancers.

Cardiovascular risks associated with protease inhibitors for the treatment of HIV.

Introduction: Cumulative use of some first-generation protease inhibitors has been associated with higher rates of dyslipidemia and increased risk of cardiovascular disease. The protease inhibitors most commonly in use are atazanavir and darunavir, which have fewer detrimental lipid effects and greater tolerability. This paper aims to review the evidence of a potential association of these contemporary protease inhibitors with the risk of ischemic CVD and atherosclerotic markers.Areas covered: We searched for publications of randomized trials and observational studies on PubMed from 1 January 2000 onwards, using search terms including: protease inhibitors; darunavir; atazanavir; cardiovascular disease; cardiovascular events; dyslipidemia; mortality; carotid intima media thickness; arterial elasticity; arterial stiffness and drug discontinuation. Ongoing studies registered on clinicaltrials.gov as well as conference abstracts from major HIV conferences from 2015-2020 were also searched.Expert opinion: Atazanavir and darunavir are no longer part of first-line HIV treatment, but continue to be recommended as alternative first line, second- and third-line regimens, as part of two drug regimens, and darunavir is used as salvage therapy. Although these drugs will likely remain in use globally for several years to come, baseline CVD risk should be considered when considering their use, especially as the population with HIV ages.

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 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 antiretroviral treatment were followed from their first BMI measurement to the first of either CVD or DM event, or earliest of January 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 2104 CVD and 1583 DM events over 365,287 and 354,898 person-years [rate: CVD 5.8/1000 (95% confidence interval: 5.5 to 6.0); DM 4.5/1000 (95% confidence interval: 4.2 to 4.7)]. Participants were largely men (74%), baseline mean age of 40 years, and median BMI of 23.0 (IQR: 21.0-25.3). A 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: Although increases in BMI across all levels of baseline BMI were not associated with an increased risk of CVD, such changes were consistently associated with an increased risk of DM. There was also some evidence of an increased risk of CVD with a decrease in BMI.

Cost-effectiveness of statins for primary prevention of atherosclerotic cardiovascular disease among people living with HIV in the United States.

BACKGROUND: Expanding statin use may help to alleviate the excess burden of atherosclerotic cardiovascular disease in people living with HIV (PLHIV). Pravastatin and pitavastatin are preferred agents due to their lack of substantial interaction with antiretroviral therapy. We aimed to evaluate the cost-effectiveness of pravastatin and pitavastatin for the primary prevention of atherosclerotic cardiovascular disease among PLHIV in the United States. METHODS: We developed a microsimulation model that randomly selected (with replacement) individuals from the Data-collection on Adverse Effects of Anti-HIV Drugs study with follow-up between 2013 and 2016. Our study population was PLHIV aged 40 to 75 years, stable on antiretroviral therapy, and not currently using lipid-lowering therapy. Direct medical costs and quality-adjusted life-years (QALYs) were assigned in annual cycles and discounted at 3% per year. We assumed a willingness-to-pay threshold of $100,000/QALY gained. The interventions assessed were as follows: (1) treating no one with statins; (2) treating everyone with generic pravastatin 40 mg/day (drug cost $236/year) and (3) treating everyone with branded pitavastatin 4 mg/day (drug cost $2,828/year). The model simulated each individual's probability of experiencing atherosclerotic cardiovascular disease over 20 years. RESULTS: Persons receiving pravastatin accrued 0.024 additional QALYs compared with those not receiving a statin, at an incremental cost of $1338, giving an incremental cost-effectiveness ratio of $56,000/QALY gained. Individuals receiving pitavastatin accumulated 0.013 additional QALYs compared with those using pravastatin, at an additional cost of $18,251, giving an incremental cost-effectiveness ratio of $1,444,000/QALY gained. These findings were most sensitive to the pill burden associated with daily statin administration, statin costs, statin efficacy and baseline atherosclerotic cardiovascular disease risk. In probabilistic sensitivity analysis, no statin was optimal in 5.2% of simulations, pravastatin was optimal in 94.8% of simulations and pitavastatin was never optimal. CONCLUSIONS: Pravastatin was projected to be cost-effective compared with no statin. With substantial price reduction, pitavastatin may be cost-effective compared with pravastatin. These findings bode well for the expanded use of statins among PLHIV in the United States. To gain greater confidence in our conclusions it is important to generate strong, HIV-specific estimates on the efficacy of statins and the quality-of-life burden associated with taking an additional daily pill.

Predictors of Ischemic and Hemorrhagic Strokes Among People Living With HIV: The D:A:D International Prospective Multicohort Study.

BACKGROUND: Hypertension is a stronger predictor of hemorrhagic than ischemic strokes in the general population. We aimed to identify whether hypertension or other risk factors, including HIV-related factors, differ in their associations with stroke subtypes in people living with HIV (PLWHIV). METHODS: HIV-1-positive individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed from the time of first blood pressure (BP) measurement after 1/1/1999 or study entry until the first of a validated stroke, 6 months after last follow-up or 1/2/2014. Stroke events were centrally validated using standardized criteria. Hypertension was defined as one systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg. Poisson and Cox proportional hazards regression models determined associations of established cerebro/cardiovascular disease and HIV-related risk factors with stroke and tested whether these differed by stroke subtype. FINDINGS: 590 strokes (83 hemorrhagic, 296 ischemic, 211 unknown) occurred over 339,979 person-years (PYRS) (incidence rate/1000 PYRS 1.74 [95% confidence interval (CI) 1.60-1.88]). Common predictors of both hemorrhagic and ischemic strokes were hypertension (relative hazard 3.55 [95% CI 2.29-5.50] and 2.24 [1.77-2.84] respectively) and older age (1.28 [1.17-1.39] and 1.19 [1.12-1.25]). Male gender (1.62 [1.14-2.31] and 0.60 [0.35-0.91]), previous cardiovascular events (4.03 [2.91-5.57] and 1.44 [0.66-3.16]) and smoking (1.90 [1.41-2.56] and 1.08 [0.68-1.71]) were stronger predictors of ischemic then hemorrhagic strokes, whereas hypertension, hepatitis C (1.32 [0.72-2.40] and 0.46 [0.30-0.70]) and estimated glomerular filtration rate < 60 mL/min/1.72 m3 (4.80 [2.47-9.36] and 1.04 [0.67-1.60]) were stronger predictors of hemorrhagic than ischemic strokes. A CD4 count < 200 cells/µL was associated with an increased risk of hemorrhagic stroke only. INTERPRETATION: Risk factors for stroke may differ by subtype in PLWHIV, emphasizing the importance of further research to increase the precision of stroke risk estimation.

Serious clinical events in HIV-positive persons with chronic kidney disease.

OBJECTIVES: Predictors of chronic kidney disease (CKD) amongst HIV-positive persons are well established, but insights into the prognosis after CKD including the role of modifiable risk factors are limited. DESIGN: Prospective cohort study. METHODS: D:A:D participants developing CKD (confirmed, >3 months apart, eGFR ≤ 60 ml/min per 1.73 m or 25% eGFR decrease when eGFR ≤ 60 ml/min per 1.73 m) were followed to incident serious clinical events (SCE); end stage renal and liver disease (ESRL and ESLD), cardiovascular disease (CVD), AIDS-defining and non-AIDS-defining malignancies (NADM), other AIDS or death, 6 months after last visit or 1 February 2016. Poisson regression models considered associations between SCE and modifiable risk factors. RESULTS: During 2.7 (IQR 1.1-5.1) years median follow-up 595 persons with CKD (24.1%) developed a SCE [incidence rate 68.9/1000 PYFU (95% confidence interval 63.4-74.4)] with 8.3% (6.9-9.0) estimated to experience any SCE at 1 year. The most common SCE was death (12.7%), followed by NADM (5.8%), CVD (5.6%), other AIDS (5.0%) and ESRD (2.9%). Crude SCE ratios were significantly higher in those with vs. without CKD, strongest for ESRD [65.9 (43.8-100.9)] and death [4.8 (4.3-5.3)]. Smoking was consistently associated with all CKD-related SCE. Diabetes predicted CVD, NADM and death, whereas dyslipidaemia was only significantly associated with CVD. Poor HIV-status predicted other AIDS and death, eGFR less than 30 ml/min per 1.73 m predicted CVD and death and low BMI predicted other AIDS and death. CONCLUSION: In an era where many HIV-positive persons require less monitoring because of efficient antiretroviral treatment, persons with CKD carry a high burden of SCE. Several potentially modifiable risk factors play a central role for CKD-related morbidity and mortality.

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study.

INTRODUCTION: There is paucity of data related to potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) among HIV-positive individuals. We investigated whether such differences exist in the observational D:A:D cohort study. METHODS: Participants were followed from study enrolment until the earliest of death, six months after last visit or February 1, 2015. Initiation of CVD interventions [lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives, invasive cardiovascular procedures (ICPs) were investigated and Poisson regression models calculated whether rates were lower among women than men, adjusting for potential confounders. RESULTS: Women (n = 12,955) were generally at lower CVD risk than men (n = 36,094). Overall, initiation rates of CVD interventions were lower in women than men; LLDs: incidence rate 1.28 [1.21, 1.35] vs. 2.40 [2.34, 2.46]; ACEIs: 0.88 [0.82, 0.93] vs. 1.43 [1.39, 1.48]; anti-hypertensives: 1.40 [1.33, 1.47] vs. 1.72 [1.68, 1.77] and ICPs: 0.08 [0.06, 0.10] vs. 0.30 [0.28, 0.32], and this was also true for most CVD interventions when exclusively considering periods of follow-up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men (LLDs: relative rate 0.83 [0.78, 0.88]; ACEIs: 0.93 [0.86, 1.01]; ICPs: 0.54 [0.43, 0.68]), except for the receipt of anti-hypertensives (1.17 [1.10, 1.25]). CONCLUSION: The use of most CVD interventions was lower among women than men. Interventions are needed to ensure that all HIV-positive persons, particularly women, are appropriately monitored for CVD and, if required, receive appropriate CVD interventions.

Differences in Virological and Immunological Risk Factors for Non-Hodgkin and Hodgkin Lymphoma.

Background: Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are increased in populations with immune dysfunction, including people living with HIV; however, there is little evidence for to what degree immunological and virological factors differently affect NHL and HL risk. Methods: Data from the Data Collection on Adverse events of Anti-HIV Drugs Study cohort were analyzed to identify independent risk factors for NHL and HL using hazard ratios (HRs), focusing on current and cumulative area under the curve (AUC) measures of immunological and virological status. Variables with different associations with NHL and HL were identified using marginal Cox models. All statistical tests were two-sided. Results: Among 41 420 people followed for 337 020 person-years, 392 developed NHL (incidence rate = 1.17/1000 person-years of follow-up [PYFU], 95% confidence interval [CI] = 1.06 to 1.30) and 149 developed HL (incidence rate = 0.44/1000 PYFU, 95% CI = 0.38 to 0.52). Higher risk of both NHL and HL was associated with lower current CD4 cell count (adjusted HR [aHR] of NHL for CD4 <100 vs > 599 cells/mm3 = 8.08, 95% CI = 5.63 to 11.61; HL = 4.58, 95% CI = 2.22 to 9.45), whereas higher current HIV viral load (aHR of NHL for HIV-VL >1000 vs < 50 copies/mL = 1.97, 95% CI = 1.50 to 2.59) and higher AUC of HIV-VL (aHR of NHL for highest vs lowest quintile = 2.91, 95% CI = 1.92 to 4.41) were associated with NHL only. Both current and AUC of HIV-VL were factors that had different associations with NHL and HL, where the hazard ratio for NHL was progressively higher than for HL with increasing HIV-VL category. Lower current CD4 cell count had a strong but similar association with both NHL and HL. Conclusions: CD4 depletion increased risk of both types of lymphomas while current and accumulated HIV-VL was associated with NHL only. This suggests that NHL development is related to both CD4 cell depletion and added immune dysfunction derived from ongoing HIV replication. This latter factor was not associated with HL risk.

Abacavir use and risk of recurrent myocardial infarction.

OBJECTIVE: To investigate the association between abacavir (ABC) use and recurrent myocardial infarction (MI) among HIV-positive people with a prior MI. DESIGN: International multicohort collaboration with follow-up from 1999 to 2016. METHODS: The rate of recurrent MI was described among D:A:D participants who experienced an index MI whilst in the study, and who remained under follow-up beyond 28 days after this MI. Follow-up was considered to the date of next MI, death, 1 February 2016 or 6 months after last clinic visit. Poisson regression models considered associations between recurrent MI and exposure to ABC (use at index MI, current post-MI exposure and cumulative exposure), before and after adjusting for calendar year. RESULTS: The 984 individuals who experienced an index MI during the study (91.3% male, median age 51 at index MI) were followed for 5312 person-years, over which time there were 136 recurrent MIs (rate 2.56/100 person-years, 95% confidence interval 2.13-2.99). Rates were 2.40 (1.71-3.09) and 2.65 (2.10-3.21)/100 person-years in those who were and were not on ABC, respectively, at the index MI, and 2.90 (2.01-3.78) and 2.44 (1.95-2.93)/100 person-years in those who were and were not currently receiving ABC, respectively, post-MI. No association was seen with recurrent MI and either cumulative exposure to ABC [relative rate 0.86 (0.68-1.10)/5 years], receipt of ABC at index MI [0.90 (0.63-1.29)] nor recent post-MI exposure to ABC [1.19 (0.82-1.71)]. CONCLUSION: Among people with a previous MI, there was no evidence for an association between use of ABC post-MI and an elevated risk of a recurrent MI.

Associations between serum albumin and serious non-AIDS events among people living with HIV.

OBJECTIVE: Lower serum albumin (sAlb) has been associated with an increased risk of mortality and AIDS among people living with HIV and may be associated with the development of serious non-AIDS events (SNAEs). We evaluated the long-term association between sAlb and the risk of SNAEs. DESIGN: Prospective multinational cohort study. METHODS: D:A:D participants without SNAEs were followed from first routine sAlb value to the first of a new SNAE [cardiovascular disease (CVD), end-stage liver disease (ESLD), end-stage renal disease (ESRD), non-AIDS malignancy (NADM), death from non-AIDS cause], AIDS-death, 6 months after last visit or 1 February 2016. Poisson regression was used to determine associations between sAlb and a new SNAE, CVD, or NADM event, with adjustment for potential confounders. Models additionally tested whether the associations were modified by age, follow-up time, smoking status, CD4 and viral load. RESULTS: Of 16 350 participants (71.8% male, median age 44 years), 1463 developed an SNAE (371 CVD, 200 ESLD, 40 ESRD, 553 NADM, 299 deaths from other non-AIDS causes) over 80 264 person-years. Increased sAlb was associated with a decreased risk of an SNAE [adjusted rate ratio per 5 g/l: SNAE 0.79 (95% confidence interval: 0.76, 0.83); CVD 0.87 (0.80, 0.94); NADM 0.88 (0.82, 0.95)]. The association did not appear to wane with additional years of follow-up (P-interaction = 0.79) but was stronger for current smokers than for never smokers (P-interaction <0.01). CONCLUSION: sAlb is a durable risk factor for SNAE. Future studies are needed to determine the mechanism underlying this association and to evaluate the value of sAlb in predictive tools.

Body Mass Index and the Risk of Serious Non-AIDS Events and All-Cause Mortality in Treated HIV-Positive Individuals: D: A: D Cohort Analysis.

BACKGROUND: The relationship between body mass index (BMI) [weight (kg)/height (m)] and serious non-AIDS events is not well understood. METHODS: We followed D:A:D study participants on antiretroviral therapy from their first BMI measurement to the first occurrence of the endpoint or end of follow-up (N = 41,149 followed for 295,147 person-years). The endpoints were cardiovascular disease (CVD); diabetes; non-AIDS-defining cancers (NADCs) and BMI-NADCs (cancers known to be associated with BMI in general population); and all-cause mortality. Using Poisson regression models, we analyzed BMI as time-updated, lagged by 1 year, and categorized at: 18.5, 23, 25, 27.5, and 30 kg/m. RESULTS: Participants were largely male (73%) with the mean age of 40 years (SD 9.7) and baseline median BMI of 23.3 (interquartile range: 21.2-25.7). Overall, BMI showed a statistically significant J-shaped relationship with the risk of all outcomes except diabetes. The relative risk (RR) for the BMI of <18.5 and >30 (95% confidence interval) compared with 23-25, respectively, was as follows: CVD: 1.46 (1.15-1.84) and 1.31 (1.03-1.67); NADCs: 1.78 (1.39-2.28) and 1.17 (0.88-1.54); and "BMI-NADCs": 1.29 (0.66-2.55) and 1.92 (1.10-3.36). For all-cause mortality, there was an interaction by sex (P < 0.001): RR in males: 2.47 (2.12-2.89) and 1.21 (0.97-1.50); and in females: 1.60 (1.30-1.98) and 1.02 (0.74-1.42). RR remained around 1 for intermediate categories of BMI. The risk of diabetes linearly increased with increasing BMI (P < 0.001). CONCLUSIONS: Risk of CVD, a range of cancers, and all-cause mortality increased at low BMI (<18.5) and then tended to increase only at BMI > 30 with a relatively low risk at BMI of 23-25 and 25-30. High BMI was also associated with risk of diabetes.