Line D. Rasmussen

Risk of cerebrovascular events in persons with and without HIV: a Danish nationwide population-based cohort study.

Objective:To assess the risk of cerebrovascular events (CVEs) in HIV-infected individuals and evaluate the impact of proven risk factors, injection drug abuse (IDU), immunodeficiency, HAART and family-related risk factors. Design:Nationwide, population-based cohort study. Methods:The study population included all Danish HIV-infected individuals, a population-based comparison cohort and parents of both cohorts – all with no prior cerebral comorbidity. We computed incidence rate ratios (IRRs) of overall CVEs and CVEs with and without proven risk factors, stratifying the analyses on IDU. Impact of immunodeficiency, HAART, protease inhibitors, indinavir, didanosin, tenofovir and abacavir on risk of CVEs was analyzed using time-dependent Cox regression analyses. Results:HIV-infected individuals had an increased risk of CVEs compared with the comparison cohorts [(non-IDU HIV adjusted IRR 1.60; 95% confidence interval [CI] 1.32–1.94), (IDU HIV adjusted IRR 3.94; 95% CI 2.16–7.16)]. The risk was increased with and without proven risk factors. A CD4 cell count of 200 cells/&mgr;l or less before the start of HAART and exposure to abacavir increased the risk of CVE [(adjusted IRR 2.26; 95% CI 1.05–4.86) and (adjusted IRR 1.66; 95% CI 1.03–2.68)]. Protease inhibitors, indinavir, didanosin, tenofovir and HAART in general had no impact. Risk of CVEs was only increased in the parents of IDU HIV-infected individuals. Conclusion:HIV-infected individuals have an increased risk of CVEs with and without proven risk factors. The risk is associated with IDU, low CD4 cell count and exposure to abacavir, but not with HAART. An association with family-related risk factors seems vague except for parents of IDU individuals.

Risk of Diabetes Mellitus in Persons with and without HIV: A Danish Nationwide Population-Based Cohort Study

Objective In a nationwide, population-based cohort study we assessed the risk of diabetes mellitus (DM) in HIV-infected individuals compared with the general population, and evaluated the impact of risk factors for DM in HIV-infected individuals. Methods We identified 4,984 Danish-born HIV-infected individuals from the Danish HIV Cohort Study and a Danish born population-based age- and gender-matched comparison cohort of 19,936 individuals (study period: 1996–2009). Data on DM was obtained from the Danish National Hospital Registry and the Danish National Prescription Registry. Incidence rate ratios (IRR) and impact of risk factors including exposure to Highly Active Antiretroviral Therapy (HAART) and antiretroviral drugs were estimated by Poisson regression analyses. Results In the period 1996–1999 risk of DM was higher in HIV-infected individuals compared to the comparison cohort (adjusted IRR: 2.83; 95%CI: 1.57–5.09), both before (adjusted IRR: 2.40; 95%CI: 1.03–5.62) and after HAART initiation (adjusted IRR: 3.24; 95% CI: 1.42–7.39). In the period 1999–2010 the risk of DM in HIV-infected individuals did not differ from that of the comparison cohort (adjusted IRR: 0.90; 95% CI: 0.72–1.13), although the risk was decreased before HAART-initiation (adjusted IRR: 0.45; 95%CI: 0.21–0.96). Increasing age, BMI and the presence of lipoatrophy increased the risk of DM, as did exposure to indinavir, saquinavir, stavudine and didanosine. Conclusion Native HIV–infected individuals do not have an increased risk of developing DM compared to a native background population after year 1998. Some antiretroviral drugs, not used in modern antiretroviral treatment, seem to increase the risk of DM.

Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study

BACKGROUND Whether the reported high risk of age-related diseases in HIV-infected people is caused by biological ageing or HIV-associated risk factors such as chronic immune activation and low-grade inflammation is unknown. We assessed time trends in age-standardised and relative risks of nine serious age-related diseases in a nationwide cohort study of HIV-infected individuals and population controls. METHODS We identified all HIV-infected individuals in the Danish HIV Cohort Study who had received HIV care in Denmark between Jan 1, 1995, and June 1, 2014. Population controls were identified from the Danish Civil Registration System and individually matched in a ratio of nine to one to the HIV-infected individuals for year of birth, sex, and date of study inclusion. Individuals were included in the study if they had a Danish personal identification number, were aged 16 years or older, and were living in Denmark at the time of study inclusion. Data for study outcomes were obtained from the Danish National Hospital Registry and the Danish National Registry of Causes of Death and were cardiovascular diseases (myocardial infarction and stroke), cancers (virus associated, smoking related, and other), severe neurocognitive disease, chronic kidney disease, chronic liver disease, and osteoporotic fractures. We calculated excess and age-standardised incidence rates and adjusted incidence rate ratios of outcomes for time after HIV diagnosis, highly active antiretroviral therapy (ART) initiation, and calendar time. The regression analyses were adjusted for age, sex, calendar time, and origin. FINDINGS We identified 5897 HIV-infected individuals and 53,073 population controls; median age was 36·8 years (IQR 30·6-44·4), and 76% were men in both cohorts. Dependent on disease, the HIV cohort had 55,050-57,631 person-years of follow-up and the population controls had 638,204-659,237 person-years of follow-up. Compared with the population controls, people with HIV had high excess and relative risk of all age-related diseases except other cancers. Overall, the age-standardised and relative risks of cardiovascular diseases, cancers, and severe neurocognitive disease did not increase substantially with time after HIV diagnosis or ART initiation. Except for chronic kidney diseases, the age-standardised and relative risks of age-related diseases did not increase with calendar time. INTERPRETATIONS Severe age-related diseases are highly prevalent in people with HIV, and continued attention and strategies for risk reduction are needed. The findings from our study do not suggest that accelerated ageing is a major problem in the HIV-infected population. FUNDING Preben og Anna Simonsens Fond, Novo Nordisk Foundation, Danish AIDS Foundation, Augustinus Foundation, and Odense University Hospitals Frie Fonds Midler.

Myocardial Infarction Among Danish HIV-Infected Individuals: Population-Attributable Fractions Associated With Smoking

BACKGROUND Human immunodeficiency virus-infected individuals have increased risk of myocardial infarction (MI); however, the contribution from smoking and potentiating effects of HIV are controversial. METHODS From the Danish HIV Cohort Study and the Copenhagen General Population Study, we identified 3251 HIV-infected individuals and 13 004 population controls matched on age and gender. Data on MI were obtained from the National Hospital Registry and the National Registry of Causes of Death. We calculated adjusted incidence rate ratios (aIRR) for risk of MI and population-attributable fractions (PAF) of MI associated with smoking. RESULTS In never smokers, HIV was not associated with an increased risk of MI (aIRR, 1.01; 95% confidence interval [CI], .41-2.54). In previous and current smokers, HIV was associated with a substantially increased risk of MI (aIRR, 1.78; 95% CI, .75-4.24 and aIRR, 2.83; 95% CI, 1.71-4.70). The PAF associated with ever smoking (previous or current) was 72% (95% CI, 55%-82%) for HIV-infected individuals and 24% (95% CI, 3%-40%) for population controls. If all current smokers stopped smoking, 42% (95% CI, 21%-57%) and 21% (95% CI, 12%-28%) of all MIs could potentially be avoided in these 2 populations. CONCLUSIONS Smoking is associated with a higher risk of MI in the HIV-infected population than in the general population. Approximately 3 of 4 MIs among HIV-infected individuals are associated with ever smoking compared with only 1 of 4 MIs among population controls. Smoking cessation could potentially prevent more than 40% of MIs among HIV-infected individuals, and smoking cessation should be a primary focus in modern HIV care.

Statin Therapy and Mortality in HIV-Infected Individuals; A Danish Nationwide Population-Based Cohort Study

Background Recent studies have suggested that statins possess diverse immune modulatory and anti-inflammatory properties. As statins might attenuate inflammation, statin therapy has been hypothesized to reduce mortality in HIV-infected individuals. We therefore used a Danish nationwide cohort of HIV-infected individuals to estimate the impact of statin use on mortality before and after a diagnosis of cardiovascular disease, chronic kidney disease or diabetes. Methods We identified all Danish HIV-infected individuals (1,738) who initiated HAART after 1 January 1998, and achieved virological suppression within 180 days. Date of first redemption of a prescription of statin was obtained from the Danish National Prescription Registry. We used Poisson regression analysis to assess adjusted mortality rate ratios (aMRR). First, time was censored at date of virological failure (VL >500 copies/ml). Second, time was not censored at virological failure. All analyses were adjusted for potential confounders. Results In the analyses confined to observation time without virological failure (+ censoring) statin therapy was associated with a non-statistically significant reduced rate of death (aMRR 0.75; 95% CI: 0.33–1.68). No difference was observed in the analysis with no censoring (aMRR 1.17; 95% CI: 0.66–2.07). Use of statin seemed to reduce mortality in individuals after a diagnosis of comorbidity {(+ censoring: aMRR: 0.34; 95% CI: 0.11–1.04), (−censoring: aMRR: 0.64; 95% CI: 0.32–1.29)}. No difference in rate of death could be detected before first date of diagnosis of comorbidity {(+ censoring: aMRR: 1.12; 95% CI: 0.34–3.62), (−censoring: aMRR: 0.90; 95% CI: 0.28–2.88)}. Conclusion Statin therapy might reduce all-cause mortality in HIV-infected individuals, but the impact on individuals with no comorbidity seems small or absent. An unambiguous proof of a causal relation can only be obtained in a randomized controlled trial, but the sample size predicted may be prohibitive for its conduct.

HIV and risk of venous thromboembolism: a Danish nationwide population‐based cohort study

The association between HIV infection and the risk of venous thromboembolism (VTE) is controversial. We examined the risk of VTE in HIV‐infected individuals compared with the general population and estimated the impact of low CD4 cell count, highly active antiretroviral therapy (HAART) and injecting drug use (IDU).

Risk of Cataract Surgery in HIV-Infected Individuals: A Danish Nationwide Population-Based Cohort Study

BACKGROUND Premature aging has been suggested a risk factor for early death in patients infected with human immunodeficiency virus (HIV). Therefore, the risk of age-related diseases, such as cataracts, should be increased in this population. In a nationwide, population-based cohort study we assessed the risk of cataract surgery in HIV-infected individuals compared with the general population. METHODS We identified 5315 HIV-infected individuals from a Danish national cohort of HIV-infected individuals and a population-based age- and sex-matched comparison cohort of 53,150 individuals. Data on cataract surgery were obtained from the Danish National Hospital registry. Cumulative incidence curves were constructed. Incidence rate ratios (IRRs) and impact of immunodeficiency, highly active antiretroviral therapy (HAART), and treatment with abacavir, tenofovir, protease inhibitors, and nonnucleoside analogue reverse-transcriptase inhibitors (NNRTIs) were estimated by Poisson regression analyses and adjusted for age, sex, and calendar year. RESULTS HIV-infected individuals had a higher risk of cataract surgery than the comparison cohort (adjusted IRR, 1.87; 95% confidence interval (CI): 1.50-2.33). The highest risk was found in patients with a CD4 cell count ≤ 200 cells/μL (adjusted IRR before HAART initiation, 3.11 [95% CI, 1.26-7.63]; adjusted IRR after HAART initiation, 4.74 [95% CI, 2.60-8.62]). In patients not receiving HAART and those receiving HAART with a CD4 cell count >200 cells/mL the adjusted IRRs were 0.60 (95% CI: 0.22-1.61) and 1.87 (95% CI: 1.46-2.39). Treatment with abacavir, tenofovir, protease inhibitors, or NNRTIs did not increase the risk substantially. CONCLUSIONS HIV-infected individuals have an increased risk of cataract surgery. The risk is mainly associated with immunodeficiency and HAART, but accelerated aging cannot be excluded as part of the possible explanation.

Risk of Myocardial Infarction in Parents of HIV-infected Individuals: a population-based Cohort Study

BackgroundPrevious studies have indicated an increased risk of myocardial infarction (MI) in HIV infected individuals especially after start of highly active antiretroviral therapy (HAART). It is however controversial whether the increased risk of atherosclerotic disease is exclusively associated with the HIV disease and HAART or whether life-style related or genetic factors also increase the risk in this population. To establish whether the increased risk of myocardial infarction in HIV patients partly reflects an increased risk of MI in their families, we estimated the relative risk of MI in parents of HIV-infected individuals.MethodsFrom the Danish HIV Cohort Study and the Danish Civil Registration System we identified the parents of all HIV-infected patients born in Denmark after 1952 in whom a Danish born mother was identifiable. For each HIV patient, 4 matched population controls and their parents were identified. Cumulative incidence functions were constructed to illustrate time to first MI of the parents as registered in the Danish National Hospital Registry. Incidence rate ratios (IRR) were estimated by Coxs regression analyses. Due to the confidential type of the analysed data the study was approved by the Danish Data Protection Agency.Results2,269 mothers and 2,022 fathers of HIV patients as well as 9,076 mothers and 8,460 fathers of control subjects were identified. We observed an increased risk of MI in mothers of HIV patients (adjusted IRR, 1.31; 95% CI: 1.08-1.60). The strongest association was seen in case the offspring was infected heterosexually (adjusted IRR, 1.59; 95% CI: 1.07-2.35) or by IV drug abuse (IVD) (adjusted IRR, 1.63; 95% CI: 1.02-2.60). In fathers of HIV patients the risk of MI was only increased if the offspring was infected by IVD (adjusted IRR, 1.42; 95% CI: 1.01-2.00).ConclusionMothers of HIV-infected patients have an increased risk of MI. We presume that this stems from family related life style risk factors, some of which may also influence the risk of MI in HIV-infected patients.

Effects of inhaled plasminogen activator on the balance between coagulation and fibrinolysis in traumatized pigs

A profibrinolytic state is normal in the alveoli, but this may change as a result of trauma, possibly leading to fibrin deposition, a characteristic of acute lung injury/acute respiratory distress syndrome. Therefore, the present study investigated in a double-blind, placebo-controlled manner the effect of severe trauma on the alveolar fibrinolytic/coagulation balance, and the effect here-upon of inhalation of single-chain urokinase plasminogen activator (scu-PA) in pigs. The study shows an increased concentration of scu-PA in the bronchoalveolar lavage fluid of the treated animals in association with an increased plasmin-dependent fibrinolytic activity without increased systemic fibrinolytic activity, the transient increase in the concentration of scu-PA in the plasma being minimal. In conclusion, the study shows that activatable scu-PA can be nebulized to the lower respiratory tract and can increase the alveolar fibrinolysis without any significant systemic effects.

HIV-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) -Mediating Antibodies Decline while NK Cell Function Increases during Antiretroviral Therapy (ART).

Understanding alterations in HIV-specific immune responses during antiretroviral therapy (ART), such as antibody-dependent cellular cytotoxicity (ADCC), is important in the development of novel strategies to control HIV-1 infection. This study included 53 HIV-1 positive individuals. We evaluated the ability of effector cells and antibodies to mediate ADCC separately and in combination using the ADCC-PanToxiLux assay. The ability of the peripheral blood mononuclear cells (PBMCs) to mediate ADCC was significantly higher in individuals who had been treated with ART before seroconversion, compared to the individuals initiating ART at a low CD4+ T cell count (<350 cells/μl blood) and the ART-naïve individuals. The frequency of CD16 expressing natural killer (NK) cells correlated with both the duration of ART and Granzyme B (GzB) activity. In contrast, the plasma titer of antibodies mediating ADCC declined during ART. These findings suggest improved cytotoxic function of the NK cells if initiating ART early during infection, while the levels of ADCC mediating antibodies declined during ART.