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CPCRA Protocol Collaborations Articles

  D:A:D Study

Weber R, Sabin CA, Friis-Møller N, Reiss P, El-Sadr WM, Kirk O, Dabis F, Law MG, Pradier C, De Wit S, Ǻkerlund B, Calvo G, d’Arminio Monforte A, Richenbach M, Ledergerber, Phillips AN, Lundgren JD. Liver-related deaths in persons infected with the human immunodeficiency virus. Arch Intern Med 2006;166:1632-1641.
This article is available as a PDF File

Background: An increasing proportion of deaths among human immunodeficiency virus (HIV)-infected persons with access to combination antiretroviral therapy (cART) are due to complications of liver diseases.
Methods: We investigated the frequency of and risk factors associated with liver-related deaths in the Data Collection on Adverse Events of Anti-HIV Drugs study, which prospectively evaluated 76,893 person-years of follow-up in 23,441 HIV-infected persons. Multivariable Poisson regression analyses identified factors associated with liver-related, AIDS-related, and other causes of death.
Results: There were 1,256 deaths (5.3%; 1.6 per 100 person-years); 14.5% were from liver-related causes. Of these, 16.9% had active hepatitis B virus (HBV), 66.1% had hepatitis C virus (HCV), and 7.1% had dual viral hepatitis co-infections. Predictors of liver-related deaths were latest CD4 cell count (adjusted relative rate [RR], 16.1; 95% confidence interval [CI], 8.1-31.7 for <50 vs >500/µL), age (RR, 1.3; 95% CI, 1.2-1.4 per 5 years older), intravenous drug use (RR, 2.0; 95% CI, 1.2-3.4), HCV infection (RR, 6.7; 95% CI, 4.0-11.2), and active HBV infection (RR.3.7; 95% CI, 2.4-5.9). Univariable analyses showed no relationship between cumulative years patients were receiving cART and liver-related death (RR, 1.00; 95% CI, 0.93-1.07). Adjustment for the most recent CD4 cell count and patient characteristics resulted in an increased risk of liver-related mortality per year of mono or dual antiretroviral therapy before cART (RR, 1.09; 95% CI, 1.02-1.16; P=.008) and per year of cART (RR, 1.11; 95% CI, 1.01-1.21; P=.02).
Conclusions: Liver-related death was the most frequent cause of non-AIDS-related death. We found a strong association between immunodeficiency and risk of liver-related death. Longer follow-up is required to investigate whether clinically significant treatment-associated liver-related mortality will develop.

Thiébaut R, El-Sadr WM, Friis-Møller N, Rickenbach M, Reiss P, D’Arminio Monforte A, Morfeldt L, Fontas E, Kirk O, De Wit S, Calvo G, Law MG, Dabis F, Sabin CA Lundgren JD for the “Data Collection of Adverse events of anti-HIV Drugs’ (D:A:D) Study Group. Predictors of hypertension and changes of blood pressure in HIV-infected patients. Antivir Ther 2005;10:811-823.
This article is available as a PDF File

Objective: We assessed predictors of changes in systolic (SBP) and diastolic (DBP) blood pressure during follow-up and of the development of hypertension in HIV-infected individuals. Methods: International cohort collaborative study (D:A:D) of established prospective cohorts of HIV-1-infected patients. Longitudinal analysis of changes in blood pressure (BP) was performed using mixed effects models in 17170 patients. Predictors of development of hypertension during follow-up (systolic BP >140 and/or diastolic BP >90mmHg or initiation of antihypertensive treatment) were assessed using Cox models in 8984 patients with a normal BP level at baseline.
Results: 73548 Bp measurements with a median of 4 per patient (interquartile range [IQR]: 2-6) were recorded over a median follow-up of 2.3 years (IQR: 1.5-2.6). Risk factors significantly associated with a development of higher systolic CP and diastolic CP (differenced >5 mmHg and P-values <0.001) during follow-up were: older age, male sex, higher body mass index (BMI) and use of BP-lowering drugs. In patients with normal BP at baseline, 1186 develop hypertension for an incidence of 72.1 per 1000 person-years (95% confidence interval : 68.2-76.0). Factors associated with development of hypertension were: male sex, higher BMI, older age, higher CP at baseline, high total cholesterol and clinical lipodystrophy. Cumulative duration of exposure to nucleoside reverse transcriptase inhibitors (P=0.75), protease inhibitors (P=0.92) as well as type of antiretroviral treatment at baseline (P=0.18) were not associated with a higher risk of hypertension. Cumulative duration of exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was significantly associated with lower risk of hypertension (hazard ratio=0.78 and 0.67 for those treated <10 months and >10 months compared with no exposure; P=0.005).
Conclusions: Increased blood pressure in HIV-infected individuals is associated with established risk factors for hypertension. There was no evidence for an independent deleterious effect of any class of antiretroviral drugs on BP, although the use of NNRTIs was associated with a lower risk of development of hypertension.

d’Armino Monforte A, Savin CA, Reiss P, Weber R, Kirk O, El-Sadr W, De Wit S, Mateu S, Petoumenos K, Davis F, Pradier C, Morfeldt L, Phillips AN, Lundgren JD, Friis-Moller N, for the D:A:D Study Group. Cardio- and cerebrovasbular events in HIV-infected persons.
AIDS May 21, 2004;18:1811-1817.
This article is available as a PDF File

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 (VI) 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 127 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 internal (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.

Fontas E, van Leth F, Sabin CA, Friis-Moller N, Rickenbach M, d'Arminio Monforte A, Kirk O, Dupon M, Morfeldt L, Mateu S, Petoumenos K, El-Sadr W, de Wit S, Lundgren JD, Pradier C, Reiss, P, for the D:A:D Study Group. Lipid Profiles in HIV-Infected Patients Receiving Combination Antiretroviral Therapy: Are Different Antiretroviral Drugs Associated with Different Lipid Profiles? J Infect Dis March 15, 2004;189:1056-74.
This article is available as a PDF File

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:HDHL-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:HDHL-c ratios than did antiretroviral-naïve patients; patients receiving 2 PIs had higher levels of each lipid. Ritonavir- containing regimens were associated with higher TC and TG levels and TC:HDHL-c ratios than were indinavir-containing regimens; however, receipt of nelfinavir was associated with reduced risk of lower HFL-c levels, and receipt of saquinavir was associated with lower TC:HDL-c ratios. Patients receiving non-nucleoside reverse-transcriptase inhibitors had higher levels of TC and LDL-c than did antiretroviral-naïve 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.

Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, Thiebaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD. Combination Antiretroviral Therapy and the Risk of Myocardial Infarction. New Engl J Med November 20, 2003;349:1993-2003.
This article is available as a PDF File

Background: It remains controversial whether exposure to combination antiretroviral treatment increases the risk of myocardial infarction.
Methods: n this prospective observational study, we enrolled 23,468 patients from 11 previously established cohorts from December 1999 to April 2001 and collected follow-up data until February 2002. Data were collected on infection with the human immunodeficiency virus and on risk factors for and the incidence of myocardial infarction. Relative rates were calculated with Poisson regression models. Combination antiretroviral therapy was defined as any combination regimen of antiretroviral drugs that included a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor.
Results: Over a period of 36,199 person-years, 126 patients had a myocardial infarction. The incidence of myocardial infarction increased with longer exposure to combination antiretroviral therapy (adjusted relative rate per year of exposure, 1.26 [95 percent confidence interval, 1.12 to 1.41]; P <0.001). Other factors significantly associated with myocardial infarction were older age, current or former smoking, previous cardiovascular disease, and male sex, but not a family history of coronary heart disease. A higher total serum cholesterol level, a higher triglyceride level, and the presence of diabetes were also associated with an increased incidence of myocardial infarction.
Conclusions: Combination antiretroviral therapy was independently associated with a 26 percent relative increase in the rate of myocardial infarction per year of exposure during the first four to sic years of use. However, the absolute risk of myocardial infarction was low ad must be balanced against the marked benefits from antiretroviral treatment.

Friis-Moller N, Weber R, Reiss P, Thiebaut R, Kirk O, d'Arminio Monforte A, et al for the DAD study group. Results from the DAD study: Cardiovascular disease risk factors in HIV patients - association with antiretroviral therapy.
AIDS May 23, 2003; 17(8):1179-1193
This article is available as a PDF File

The purpose of the D:A:D Study is to determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-infected persons, to investigate any association between such risk factors, stage of HIV disease, and use of antiretroviral therapies, and to follow patients for the possible development of cardiovascular events. The initial study results which reports the baseline information about these patients being followed for the next few years were reported at the Retrovirus Conference in Feb 2003 and now an official publication current issue of the journal AIDS. This initial look at the patients and potential risk factors includes examining levels of cholesterol, triglycerides, diabetes, hypertension, the types of HAART regimens patients are taking, and body changes & their association with lipid abnormalities.