Nina Friis-Møller

Cardiovascular disease risk factors in HIV patients - association with antiretroviral therapy. Results from the DAD study

Objective: To determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-infected persons, and to investigate any association between such risk factors, stage of HIV disease, and use of antiretroviral therapies. Design: Baseline data from 17 852 subjects enrolled in DAD, a prospective multinational cohort study initiated in 1999. Methods: Cross-sectional analyses of CVD risk factors at baseline. The data collected includes data on demographic variables, cigarette smoking, diabetes mellitus, hypertension, dyslipidaemia, body mass index, stage of HIV infection, antiretroviral therapy. Results: Almost 25% of the study population were at an age where there is an appreciable risk of CVD, with those receiving a protease inhibitor (PI) and/or non-nucleoside reverse transcriptase inhibitor (NNRTI) tending to be older. 1.4% had a previous history of CVD and 51.5% were cigarette smokers. Increased prevalence of elevated total cholesterol (⩾ 6.2 mmol/l) was observed among subjects receiving an NNRTI but no PI [odds ratio (OR), 1.79; 95% confidence interval (CI), 1.45–2.22], PI but no NNRTI (OR, 2.35; 95% CI, 1.92–2.87), or NNRTI + PI (OR, 5.48; 95% CI, 4.34–6.91) compared to the prevalence among antiretroviral therapy (ART)-naive subjects. Subjects who have discontinued ART as well as subjects receiving nucleoside reverse transcriptase inhibitors had similar cholesterol levels to treatment-naive subjects. Higher CD4 cell count, lower plasma HIV RNA levels, clinical signs of lipodystrophy, longer exposure times to NNRTI and PI, and older age were all also associated with elevated total cholesterol level. Conclusion: HIV-infected persons exhibit multiple known risk factors for CVD. Of specific concern is the fact that use of the NNRTI and PI drug classes (alone and especially in combination), particularly among older subjects with normalized CD4 cell counts and suppressed HIV replication, was associated with a lipid profile known to increase the risk of coronary heart disease.

Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration

BACKGROUND Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients. METHODS We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals. FINDINGS Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir). INTERPRETATION There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation.Methods: Biomarkers, ischemic changes on the electrocardiogram, and rates of various predefined types of cardiovascular disease (CVD) events according to NRTIs used were explored in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. Patients receiving abacavir and not didanosine were compared with those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine (other NRTIs). Patients randomly assigned to the continuous antiretroviral therapy arm of SMART were included in all analyses (N1⁄42752); for the study of biomarkers, patients from the antiretroviral therapy interruption arm were also included.

Incidence and Risk Factors for New-Onset Diabetes in HIV-Infected Patients: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study

OBJECTIVE—The aims of this study were to determine the incidence of diabetes among HIV-infected patients in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort, to identify demographic, HIV-related, and combination antiretroviral therapy (cART)-related factors associated with the onset of diabetes, and to identify possible mechanisms for any relationships found. RESEARCH DESIGN AND METHODS—D:A:D is a prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point. Poisson regression models were used to assess the relation between diabetes and exposure to cART after adjusting for known risk factors for diabetes, CD4 count, lipids, and lipodystrophy. RESULTS—Over 130,151 person-years of follow-up (PYFU), diabetes was diagnosed in 744 patients (incidence rate of 5.72 per 1,000 PYFU [95% CI 5.31–6.13]). The incidence of diabetes increased with cumulative exposure to cART, an association that remained significant after adjustment for potential risk factors for diabetes. The strongest relationship with diabetes was exposure to stavudine; exposures to zidovudine and didanosine were also associated with an increased risk of diabetes. Time-updated measurements of total cholesterol, HDL cholesterol, and triglycerides were all associated with diabetes. Adjusting for each of these variables separately reduced the relationship between cART and diabetes slightly. Although lipodystrophy was significantly associated with diabetes, adjustment for this did not modify the relationship between cART and diabetes. CONCLUSION—Stavudine and zidovudine are significantly associated with diabetes after adjustment for risk factors for diabetes and lipids. Adjustment for lipodystrophy did not modify the relationship, suggesting that the two thymidine analogs probably directly contribute to insulin resistance, potentially through mitochondrial toxicity.

Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study.

Objective:To investigate any emerging trends in causes of death amongst HIV-positive individuals in the current cART era, and to investigate the factors associated with each specific cause of death. Design:An observational multicentre cohort study. Methods:All HIV-positive individuals included in one of the cohorts in the Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study were included. The association between HIV-specific and non HIV-specific risk factors and death were studied using multivariable Poisson regression. Results:We observed 2482 deaths in 180 176 person-years (PY) on 33 308 individuals [rate/1000 PY = 13.8 (95% CI 13.2–14.3)]. Primary causes of death were: AIDS (n = 743; rate/1000 PY = 4.12), liver-related (341; 1.89), CVD-related (289; 1.60), non-AIDS malignancy (286; 1.59). The overall rate of death fell from 16.9 in 1999/2000 to 9.6/ 1000 PY in 2007/2008. Smoking was associated with CVD and non-AIDS cancers, HBV and HCV co-infection with liver-related deaths, and hypertension with liver-related and CVD deaths. Diabetes was a risk factor for all specific causes of death except non-AIDS cancers, and higher current HIV RNA for AIDS-related deaths. Lower CD4 cell counts were associated with a higher risk of death from all specific causes of death. Conclusion:Multiple potentially modifiable traditional and HIV-specific risk factors for death of HIV-infected persons were identified. The maximum reduction in mortality in HIV-infected populations will require that each of these factors be appropriately addressed. No trends in terms of emerging causes of unexpected deaths were observed, although monitoring will continue.

Lipid Profiles in HIV-Infected Patients Receiving Combination Antiretroviral Therapy: Are Different Antiretroviral Drugs Associated with Different Lipid Profiles?

Levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c), as well as the TC:HDL-c ratio, were compared in patients receiving different antiretroviral therapy regimens. Patients receiving first-line regimens including protease inhibitors (PIs) had higher TC and TG levels and TC : HDL-c ratios than did antiretroviral-naive patients; patients receiving 2 PIs had higher levels of each lipid. Ritonavir-containing regimens were associated with higher TC and TG levels and TC : HDL-c ratios than were indinavir-containing regimens; however, receipt of nelfinavir was associated with reduced risk of lower HDL-c levels, and receipt of saquinavir was associated with lower TC : HDL-c ratios. Patients receiving nonnucleoside reverse-transcriptase inhibitors had higher levels of TC and LDL-c than did antiretroviral-naive patients, although the risk of having lower HDL-c levels was lower than that in patients receiving a single PI. Efavirenz was associated with higher levels of TC and TG than was nevirapine.

The use of the Framingham equation to predict myocardial infarctions in HIV-infected patients: comparison with observed events in the D : A : D Study

The D:A:D (Data Collection on Adverse Events of Anti‐HIV Drugs) Study, a prospective observational study on a cohort of 23 468 patients with HIV infection, indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). However, it remains unclear whether the observed increase in the rate of MI in this population can be attributed to changes in conventional cardiovascular risk factors.

Incidence and risk factors for new onset diabetes mellitus in HIV infected patients: the D:A:D study

OBJECTIVE—The aims of this study were to determine the incidence of diabetes among HIV-infected patients in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort, to identify demographic, HIV-related, and combination antiretroviral therapy (cART)-related factors associated with the onset of diabetes, and to identify possible mechanisms for any relationships found. RESEARCH DESIGN AND METHODS—D:A:D is a prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point. Poisson regression models were used to assess the relation between diabetes and exposure to cART after adjusting for known risk factors for diabetes, CD4 count, lipids, and lipodystrophy. RESULTS—Over 130,151 person-years of follow-up (PYFU), diabetes was diagnosed in 744 patients (incidence rate of 5.72 per 1,000 PYFU [95% CI 5.31–6.13]). The incidence of diabetes increased with cumulative exposure to cART, an association that remained significant after adjustment for potential risk factors for diabetes. The strongest relationship with diabetes was exposure to stavudine; exposures to zidovudine and didanosine were also associated with an increased risk of diabetes. Time-updated measurements of total cholesterol, HDL cholesterol, and triglycerides were all associated with diabetes. Adjusting for each of these variables separately reduced the relationship between cART and diabetes slightly. Although lipodystrophy was significantly associated with diabetes, adjustment for this did not modify the relationship between cART and diabetes. CONCLUSION—Stavudine and zidovudine are significantly associated with diabetes after adjustment for risk factors for diabetes and lipids. Adjustment for lipodystrophy did not modify the relationship, suggesting that the two thymidine analogs probably directly contribute to insulin resistance, potentially through mitochondrial toxicity.

Predicting the risk of cardiovascular disease in HIV-infected patients: the Data collection on Adverse Effects of Anti-HIV Drugs Study

Aims HIV-infected patients receiving combination antiretroviral therapy may experience metabolic complications, potentially increasing their risk of cardiovascular diseases (CVDs). Furthermore, exposures to some antiretroviral drugs seem to be independently associated with increased CVD risk. We aimed to develop cardiovascular risk-assessment models tailored to HIV-infected patients. Methods and results Prospective multinational cohort study. The data set included 22 625 HIV-infected patients from 20 countries in Europe and Australia who were free of CVD at entry into the Data collection on Adverse Effects of Anti-HIV Drugs Study. Using cross-validation methods, separate models were developed to predict the risk of myocardial infarction, coronary heart disease, and a composite CVD endpoint. Model performance was compared with the Framingham score. The models included age, sex, systolic blood pressure, smoking status, family history of CVD, diabetes, total cholesterol, HDL cholesterol and indinavir, lopinavir/r and abacavir exposure. The models performed well with area under the receiver operator curve statistics of 0.783 (range 0.642–0.820) for myocardial infarction, 0.776 (0.670–0.818) for coronary heart disease and 0.769 (0.695–0.824) for CVD. The models estimated more accurately the outcomes in the subgroups than the Framingham score. Conclusion Risk equations developed from a population of HIV-infected patients, incorporating routinely collected cardiovascular risk parameters and exposure to individual antiretroviral therapy drugs, might be more useful in estimating CVD risks in HIV-infected persons than conventional risk prediction models.

Cardio- and cerebrovascular events in HIV-infected persons

Objective: Recent results from the D:A:D Study indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). The present study was performed to investigate whether this risk was similar when including other cardio- and cerebro-vascular disease events (CCVE). Design: D:A:D is an international collaboration of 11 cohorts, following 23 468 HIV-infected patients prospectively at 188 clinics in 21 countries situated in Europe, USA and Australia. Methods: The end-point was the occurrence of a first CCVE during prospective follow-up, defined as the first of: acute MI, invasive cardiovascular procedures, stroke, or death from other cardiovascular disease. Relative rates (RR) for CCVE from Poisson regression models and 95% confidence intervals (CI) are reported. All models are adjusted for other risk factors for CCVE, including age, gender, ethnicity, family history, body mass index, and smoking status as well as cohort and HIV transmission group. Results: Over 36 145 person-years of follow-up, 207 patients experienced at least one CCVE (23.7% fatal). The first event was MI in 126 patients, invasive cardiovascular procedure in 39 patients, stroke in 38 patients, and death from other cardiovascular disease in four patients. The incidence of first CCVE was 5.7 per 1000 person-years [95% confidence interval (CI) 5.0–6.5] and increased with longer exposure to CART (RR per year of exposure, 1.26; 95% CI, 1.14–1.38; P < 0.0001). Conclusion: CART increases the risk of CCVD, and this increase is comparable with how CART affects the risk of MI. This finding is consistent with the hypothesis that atherosclerosis is a side-effect of CART.

Modelling the 3-year risk of myocardial infarction among participants in the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study

To estimate the 3‐year risk of myocardial infarction (MI) among participants in the Data Collection on Adverse Events of Anti‐HIV Drugs (DAD) study.