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

BACKGROUND: 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. OBJECTIVE: To compare the number of MIs observed among participants in the D:A:D Study with the number predicted by assuming that conventional cardiovascular risk equations apply to patients with HIV infection. METHODS: The Framingham equation, a conventional cardiovascular risk algorithm, was applied to individual patient data in the D:A:D Study to predict rates of MI by duration of CART. A series of sensitivity analyses were performed to assess the effect of model and data assumptions. Predictions were extrapolated to provide 10-year risk estimates, and various scenarios were modelled to assess the expected effect of different interventions. RESULTS: In patients receiving CART, the observed numbers of MIs during D:A:D follow up were similar to or somewhat higher than predicted numbers: 9 observed vs 5.5 events predicted, 14 vs 9.8, 22 vs 14.9, 31 vs 23.2 and 47 vs 37.0 for<1 year, 1-2 years, 2-3 years, 3-4 years and >4 years CART exposure, respectively. In patients who had not received CART, the observed number of MIs was fewer than predicted (3 observed vs 7.6 predicted). Nine per cent of the study population have a predicted 10-year risk of MI above 10%, a level usually associated with initiation of intervention on risk factors. CONCLUSIONS: A consistent feature of all analyses was that observed and predicted rates of MI increased in a parallel fashion with increased CART duration, suggesting that the observed increase in risk of MI may at least in part be explained by CART-induced changes in conventional risk factors. These findings provide guidance in terms of choosing lifestyle or therapeutic interventions to decrease those risk factors in much the same way as in persons without HIV infection.

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.

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.

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

OBJECTIVES: 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. METHODS: Conventional cardiovascular risk equations were applied to baseline data from the DAD study to estimate the 3-year risk of MI. Best estimates were obtained by simply applying the risk equations, with upper and lower limits based on worst case and optimistic case scenarios. Three-year risks of AIDS or death were also estimated based on a prognostic scoring system for patients receiving antiretroviral (ARV) treatment, and on estimated AIDS rates in untreated people with HIV for those patients not on ARVs or if they were to cease ARVs. RESULTS: Analyses were based on 17 600 patients (24.3% female) recruited into the DAD study with baseline data and no previous MI. The overall 3-year risk of MI was estimated to be 0.72% (lower limit 0.35, upper limit 1.12%), corresponding to a total predicted 127 (65-197) MIs over a 3-year follow-up period. The risk was much greater for men than women (0.92% vs. 0.07%), with only three (2-8) MIs predicted in women. The 3-year risk of MI was estimated to increase from 0.30% (0.20-0.38%) in ARV naive patients to 1.07% (0.43-1.77%) in patients receiving ARVs from all three drug classes. The estimated 3-year risk of AIDS or death was in the range 6.2% to 11.1% in patients receiving ARVs if they continued treatment, and 22.5% to 29.4% if they ceased ARVs. DISCUSSION: These models suggest that although the increase in relative risk of MI as a result of ARV treatment may be as high as threefold in a worst case scenario, the absolute risk is modest with a best estimate of 3-year risk less than or equal to 1% in all groups of patients, and is outweighed by the benefits of ARV treatment in terms of reduced risk of AIDS and death in most patients. As estimates are based on models not validated for people receiving ARV drugs, all estimates should be interpreted cautiously.

Analysis of PCR as a tool for detection of JC virus DNA in cerebrospinal fluid for diagnosis of progressive multifocal leukoencephalopathy.

Two polyomaviruses, JC virus (JCV) and BK virus (BKV), affect humans. JCV is the causative agent of progressive multifocal leukoencephalopathy (PML), and detection of JCV in the central nervous system (CNS) is a prerequisite for confirmation of the disease. BKV is generally not associated with neurological disease, but involvement of BKV in patients with CNS disorders has been reported. In the present study polyomavirus DNA was detected by a nested PCR at a sensitivity corresponding to the detection of 10 copies of JCV DNA in 10 microliters of cerebrospinal fluid (CSF). CSF samples from 212 patients with neurological symptoms and immunodeficiencies were investigated for the presence of polyomavirus DNA. Of 128 human immunodeficiency virus (HIV)-infected patients, 14 (11%) had JCV DNA in their CSF, and all 14 patients had clinical PML. BKV DNA was detected in one HIV-infected patient with neurological symptoms not compatible with PML. Among 84 HIV-negative patients, 6 (7%) had detectable JCV DNA in their CSF, confirming PML in patients with clinical conditions of T-cell lymphoma, chronic lymphatic leukemia, status postliver transplantation, congenital immunodeficiency, sarcoidosis, and immunodeficiency of unknown origin. The specificity of the PCR was confirmed by a clinical follow-up study which showed full agreement between the detection of JCV DNA in CSF and clinically manifest PML. The described PCR is a rapid, reproducible, and easily performed assay.

An eleven year follow-up of delayed-type hypersensitivity testing for the identification of HIV-1 infected patients at increased risk of developing AIDS.

The objective of this study was to investigate whether testing of delayed-type hypersensitivity (DTH) to recall antigens could be used to identify HIV-1 infected patients at increased risk of death or developing AIDS. Eighty-five HIV-1 infected Swedish homosexual men were tested for DTH using a commercially available kit with 7 recall antigens (Multitest, Mérieux). The patients were followed prospectively for 11 years or until death. The 11-year actuarial progression rate to AIDS was 69% and to death 60%. Older age was identified as a factor predisposing to rapid progression independent of cell-mediated immunity measured by DTH. Patients with a subnormal DTH had a significantly more rapid progression to AIDS and death than did patients with normal DTH, and the time between AIDS diagnosis and death was shorter. For patients with a multiscore (MS) < 10 mm, the median time to AIDS was 59 months, the median time to death 88 months, and the median time from AIDS diagnosis to death 11 months, compared to 106, 139, and 25 months, respectively, for patients with MS > or = 10 mm. Of the individual antigens, only a negative reaction to tuberculin was independently predictive of progression to all 3 endpoints, while a negative reaction to tetanus was independently predictive of progression to death. Thus, determination of DTH improves the early recognition of patients at increased risk of progressive disease.

Long-term remission of Kaposi's sarcoma following foscarnet treatment in HIV-infected patients.

Five patients with HIV-associated Kaposi's sarcoma (epidemic KS) were treated with foscarnet 180 mg/kg/day i.v. for 10 days. Four of them suffered from severe immunodeficiency with CD4 cell counts below 30 x 10(6)/l. Three of the patients went into long-term remission of KS. One patient was free of relapse for 12 months and 2 patients are still in remission after an observation period of 13 and 20 months respectively. The results suggest a possible role of foscarnet in the treatment of epidemic KS.

Plasma clearance of intravenous fat emulsion in acute bacterial infections.

A variety of abnormalities in lipid metabolism during infection have been reported and it has been questioned whether intravenous fat emulsion should be given in septic states. This study was designed to investigate the removal of a fat emulsion from plasma during septicaemia. An intravenous fat tolerance test (0.1 g of fat in the form of Intralipid 10% per kg b.w.) was performed in 28 adult patients who had been admitted for suspected septicaemia. All patients were febrile (mean body temperature 38.9 +/- 0.1 degrees C SEM), the majority had leucocytosis (mean value 10.5 +/- 1.0 10 (9)1 ) and all were haemodynamically stable. On the basis of bacterial cultures taken from various locations, the patients were classified as septic (n = 12; gram-negative sepsis, n = 8; gram-positive sepsis, n = 4), infected but without septicaemia (n = 9) or febrile of unknown cause (all cultures negative, n = 7). Plasma fractional removal rates of intravenous fat were similar in the different groups. The mean plasma clearance rate of intravenous fat was 6.6 +/- 0.5 (% minute), which does not differ from that reported for healthy controls. All patients with proven septicaemia and 5 non-septic patients were studied two weeks later when their infection had been treated and they were off antibiotic medication. The plasma clearance rate of i.v. fat was significantly lower in the recovery phase than during the acute febrile state (5.9 +/- 0.5 vs 4.2 +/- 0.4 %/min, n = 17; p < 0.05). It is concluded that clearance of intravenous fat emulsions from plasma is unimpaired in haemodynamically stable patients with septicaemia or other acute infections.