Eurjmedres10-suppl iii

Clinical Significance of Lipoprotein Disorders Klinikum Großhadern – Munich – Germany Clinical significance of lipid parameters as cardiovascular risk factor I
P. Reiss (Amsterdam, The Netherlands) and W. O. Richter ( Munich, Germany) Effect of HIV and its treatment on lipids – an introductory overviewP. Reiss (Amsterdam, The Netherlands) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 Changes in carotid intima-media thickness in HIV-infected patients included in the ANRS CO3Aquitaine Cohort, 1999 – 2004R. Thiébaut, V. Aurillac-Lavignolle, F. Bonnet, N. Ibrahim, C. Cipriano, D. Neau, M. Dupon, F. Dabis, P. Mercie, and the Groupe d’Epidemiologie Clinique du Sida en Aquitaine (GECSA) (Bordeaux, France) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 What is proved for low HDL-cholesterol as cardiovascular risk factor?M. Hersberger (Zurich, Switzerland) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 Changes of HDL concentration, composition and metabolism in HIV-infected patientsC. Alonso-Villaverde (Reus, Spain) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 Lipoprotein pattern in HIV-infected patients before starting antiretroviral therapy with lopinavir/riton-avirL. Magenta, W. O. Richter, M. Opravil, M. Flepp, O. Keiser, H. Bucher, H. Drechsler, P. Schmid, J. M. Evison, B. Bernasconi, E. Bernasconi (Lugano, Zurich, Lausanne, Basle, St Gallen, Bern, Mu-nich; Switzerland, Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 Remnant lipoproteins and atherosclerosisG. Dallinga-Thie (Rotterdam, The Netherlands) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 VLDL concentration, composition and metabolism of triglyceride-rich lipoproteins (remnants) in HIV-infected patientsS. Mauss (Duesseldorf, Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 Genetic factors and susceptibility to antiretroviral therapy-associated lipid disordersP. Tarr (Lausanne, Switzerland) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 Clinical significance of lipid parameters as cardiovascular risk factor II
M. Hersberger (Zurich, Switzerland) and A. Weizel (Mannheim, Germany) What is proved for lipoprotein (a) as cardiovascular risk factor?A. Weizel (Mannheim, Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 Lipoprotein (a) concentration in HIV-infected patientsT. Niehues, J. Neubert, N. Thiemeyer (Duesseldorf, Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Importance of non-lipid risk factors for coronary heart disease in HIV-infected patientsT. Neumann (Essen, Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Impact of lipodystrophy on lipids in HIV-infected patientsA. Milinkovic (Barcelona, Spain) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9 Accumulation of dorsocervical fat (“buffalo hump”) in HIV-infected patients. A case control study(Lipocer Study)R. Palacios, M. J. Galindo, J. A. Arranz, F. Lozano, V. Estrada, A. Rivero, D. Morales, V. Asensi,A. del Arco, A. Munoz, J. Santos, for the Grupo de Estudio des Alteraciones Metabólicas (GEAM)(Málaga, Valencia, Alcalá de Henares, Sevilla, Madrid, Córdoba, Oviedo, Marbella, Badajoz; Spain) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 Metabolic abnormalities and lipodystrophy syndrome in HIV-infected children in PolandJ. Popielska, M. Marczynska, S. Dobosz, R. Tyneiec (Warsaw, Poland) . . . . . . . . . . . . . . . . . . . .10 Clinical endpoints
S. Bozzette (San Diego, USA) and F.-D. Goebel (Munich, Germany) Extended follow-up of cardiovascular and cerebrovascular outcomes and deaths in a retrospective cohort ofHIV patients treated in US Veterans Affairs HospitalsS. Bozzette (San Diego, USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11 Hospitalizations for coronary heart disease and myocardial infarction among Northern-California menwith and without HIV-1 infectionD. Klein, L. Hurley, C. Quesenberry, S. Sidney (Oakland, USA) . . . . . . . . . . . . . . . . . . . . . . . .11 Relationship between prolonged exposure to combination antiretroviral therapy and myocardial infarction:effect of sex, age and lipid changes. Results from the D:A:D StudyN. Friis-Møller (Copenhagen, Denmark) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12 Effect of HIV and its treatment on lipids
should be part of the initial patient assessment prior to initiating antiretroviral therapy. Determination of lipid levels, an asses-sment of cardiovascular risk factors (e. g. smoking, diet, family Academic Medical Center, Amsterdam, The Netherlands; history), and identification of comorbid and/or preexisting con- ditions (e. g. diabetes, hypertension, obesity) are integral to this Early in the natural course of HIV infection, as seen in other in- evaluation. In those found to be at significant risk (e. g. accor- fections and chronic inflammatory conditions, plasma total cho- ding to Framingham or PROCAM algorithms), smoking cessati- lesterol, HDL- and LDL-cholesterol concentrations decrease. In on should be emphasized as an important intervention to im- addition, the size of LDL particles is also reduced resulting in an prove long-term outcomes. In addition, low-dose aspirin may be increase of more atherogenic small dense LDL particles. Finally, recommended to patients who do not have contraindications.
when patients progress to AIDS plasma triglyceride concentrati- Patients should be assisted so that they can follow National ons tend to rise. Thus, although not proven, untreated HIV in- Cholesterol Education Program (NCEP) or other guidelines fection in and of itself, may be associated with increased athero- with regard to dietary and lifestyle changes. When diet and life- genesis, the risk of which theoretically could be reduced by trea- style changes do not produce sufficient improvements in the li- pid profile, the use of lipid-lowering agents or changing the anti- Combination antiretroviral therapy (cART) for HIV is often retroviral regimen should be considered. Preliminary data indi- associated with several metabolic abnormalities, including chan- cate that substituting atazanavir, abacavir, nevirapine, or efavi- ges in blood lipids. First generation protease inhibitor (PI)-con- renz for a PI and substituting abacavir or tenofovir for stavudi- taining regimens were amongst the first recognized as being as- ne can improve lipid profiles in patients with established dyslipi- sociated with rises in total and LDL-cholesterol (LDL-C), as demia; however, there is also evidence to suggest that changing well as triglycerides. PI’s differ with respect to their effect on li- therapy alone may not achieve goals as set by NCEP or other pids, with full-dose ritonavir having the most pronounced effec- guidelines. Recent findings from a randomized trial in which ts, most notably on triglycerides. Although still present, ritona- subjects with viral suppression to < 50 copies/ml on a PI regi- vir’s effect on lipids is clearly less when used in low dose in or- men who also had mixed hyperlipidemia have suggested that ad- der to boost plasma exposure of other PI’s, which basically is ding lipid-lowering therapy—with either pravastatin or bezafi- the sole way the drug is currently still used.
brate—may result in a greater reduction in total cholesterol and It is key to realize that these changes in lipids observed with triglyceride than switching the PI to a nonnucleoside reverse PI-based therapy are greater than may be explained by the “re- transcriptase inhibitor (NNRTI)—either nevirapine or efavi- storation of health” phenomenon one would expect to result renz. The following cautions however apply when considering from suppressing HIV. In view of these effects, and the finding to add lipid-lowering therapy to antiretroviral treatment which that a high proportion of HIV-infected patients have other risk includes a PI. Fibrates, fluvastatin, and pravastatin have low po- factors for heart disease, including hypertension, smoking, dia- tential for untoward interactions with PIs, but lovastatin and betes, age older than 50 years, male sex, and pre-existing dyslipi- simvastatin should be avoided. Statin-fibrate combinations or demia, it is not surprising that after the widespread introduction atorvastatin should be used with caution. Clinical utility of long- of protease inhibitors (PIs) in 1996, the incidence of myocardial acting niacin may be limited because of its association with wor- infarction (MI) in HIV-infected patients exposed to combinati- on antiretroviral therapy or cART (often including PI) appears Finally, if possible within the framework of the primary goal to have increased. Although is has now been clearly documented of achieving sustained HIV suppression, the initial choice of an- that the risk of MI continues to increase with longer exposure to tiretroviral regimen should be one that minimizes the risk of tre- cART, the absolute risk of MI remains low and does not out- atment-related dyslipidemia, insulin resistance and changing in weigh the marked effectiveness of combination antiretroviral body fat distribution, particularly in those patients with a high a- therapy in preventing HIV-related complications. Thus, clinici- prior risk of cardiovascular disease.
ans should never withhold cART from any patient with an indi-cation to commence treatment for preventing HIV disease pro-gression.
Changes in carotid intima-media thickness in
Interestingly, initiating treatment with non-nucleoside reverse HIV-infected patients included in the ANRS CO3
transcriptase inhibitor-containing regimens has been shown to Aquitaine Cohort, 1999-2004
result in a different lipid profile, characterized most notably bymarked rises in HDL-cholesterol against the background of les- Rodolphe Thiébaut 1,2, Valérie Aurillac-Lavignolle 2, Fabrice ser rises in total cholesterol, LDL-cholesterol, and triglycerides.
Bonnet 2,3, Nagi Ibrahim 4, Claire Cipriano 3,4, Didier Neau 3, Michel Dupon 3, François Dabis 2,3, Patrick Mercié 2,3 and the Groupe The HDL-c increase has been investigated extensively for nevi- d’Epidemiologie Clinique du Sida en Aquitaine (GECSA) 2,3 rapine (NVP), and somewhat less for efavirenz (EFV). In bothinstances the rise in HDL-c results from an increase in the con- 1 INSERM EMI 0338 and 2INSERM U593, ISPED, Université centration of large HDL particles, which may be expected to Victor Segalen Bordeaux 2, 33076 Bordeaux, France, 3 Centre provide protection against atherogenesis. Preliminary studies d’Information et de Soins de l’Immunodéficience Humaine using intima-media (IMT) thickness of the carotid artery as a (CISIH), 4 Service des explorations fonctionnelles cardio-vascu- surrogate marker of atherosclerosis, seem to suggest a lower laires, Centre Hospitalier Universitaire (CHU), Bordeaux 33075 Bordeaux, France; atherogenic propensity in patients treated with ART containingnevirapine rather than a PI. Currently, there are no robust car- Measurement of carotid artery intima-media thickness (IMT) diovascular endpoint data concerning potential differences bet- with high-resolution B-mode ultrasound is a non-invasive me- ween different cART regimens with respect to CVD risk. thod for assessing atherosclerosis and tracking its progression.
Clinicians should approach cardiovascular disease prevention Its fair reproducibility and validity have been demonstrated and management in a manner similar to that for non-HIV-infec- (Grobbee 1994, Kanters 1997). In the general population, IMT ted individuals.The evaluation for dyslipidemia and cardiac risk increases with age of about 0.01mm/year (Howard 1993) and an IMT increase of 0.1 mm increases the risk of coronary events by What is proved for low HDL as cardiovascular
risk factor?
In 1999, we designed a prospective study involving partici- pants of the Aquitaine Cohort (Southwestern, France), all infec-ted with HIV-1. In- or out-patients of four participating clinical Institute of Clinical Chemistry, University Hospital, Zurich, units were consecutively enrolled if they agreed and signed a consent form. All participants were studied for IMT measure- Numerous clinical and epidemiological studies have demonstra- ment, HIV risk factors and other well known cardiovascular risk ted the inverse and independent association between HDL-cho- factors on three occasions: a baseline assessment (M0), after lesterol (HDL-C) and the risk of fatal and non-fatal coronary one-year (M12) and three years (M36) follow-up. Results have heart disease (CHD) events. From data of population studies, it already been reported (Mercié 2002, in press, Thiébaut 2005).
has been calculated that every 0.026 mmol/l (every 1 mg/dl) in- At baseline, 423 HIV-infected patients were enrolled in the crease in HDL-C lowers coronary risk by 1%. In patients with study. Median carotid IMT was 0.54 mm [0.50-0.60]. In univa- angiographically assessed CHD this association may even be riate linear regression, IMT was significantly increased (p < stronger since the prospective and multicentric European Con- 0.05) with older age, male gender, higher body mass index, hig- certed Action on Thrombosis and Disabilities (ECAT) study, as her waist-to-hip ratio, increased systolic blood pressure, total well as the Baltimore Longitudinal Heart Study identified low cholesterol, glucose disorders and homocysteine, regular smo- HDL-C as the most important biochemical risk factor for coro- king and alcohol consumption, lipodystrophy and HAART ex- posure. In a multivariate analysis, the effect of lipodystrophy However, it is not clear whether this rule can be extrapolated and HAART disappeared after adjustment for other cardiovas- to the whole range of HDL-C. Whereas a low HDL-C level (e. g.
< 20th percentile) has been consistently found to increase car- At M12, 346 patients were investigated and we observed a sig- diovascular risk, it has not been consistently shown that a high nificant increase of IMT (+ 0.02 mm, p < 0.0001). Surprisingly, HDL-C level is protective. In certain metabolic conditions a only CD4+ cell count at M0 was statistically associated to the high level of HDL-C is rather associated with excess cardiovas- variation of IMT from M0 to M12 (p < 0.001). We studied the cular risk. Hypertriglyceridemic participants of the Copenhagen change in IMT throughout follow-up on the 233 patients who City Heart Study and the PROCAM Study with high levels of had three available measurements over the three-year follow-up HDL-C were at higher coronary risk than hypertriglyceridemic period. Between M12 and M36, we observed a significant probands with intermediate HDL levels. Interestingly, although decrease of median IMT from 0.57 to 0.53 mm (p < 0.0001).
low HDL-C is also significantly associated with reduced life ex- This decrease of IMT was concomitant with an increased preva- pectancy, HDL-C levels in the fifth quintile were also associated lence of treatment with lipid lowering agents and protease inhi- with excess mortality as compared to intermediate HDL levels bitor-free HAART regimens while the smoking prevalence in the PROCAM and also in a Belgian study population. decreased. Only a marginal association between IMT decrease Low HDL-C is frequently confounded with hypertriglyceride- mia, the presence of small dense LDL, impaired glucose toleran-ce or overt diabetes mellitus type 2, hypertension, and over- weight. Actually, in many populations a low HDL-C is a typical Grobbee DE, Bots ML Carotid artery intima-media thickness component of the metabolic syndrome or insulin resistance syn- as an indicator of generalized atherosclerosis. J Intern Med drome which precedes the manifestation of the other compo- nents including diabetes. Thus, although the association of Howard G, Sharrett A, Heiss G Carotid artery intima-medial HDL-C with CHD is statistically independent of other risk fac- thickness. Distribution in general populations as evaluated tors, a low HDL-C is frequently not the sole risk factor in a gi- by B-mode ultrasound. Stroke 1993; 24: 297-1304.
Kanters S, Alga A, van Leeuwen MS, et al Reproducibility of ven individual. Therefore, elimination of additional risk factors in vivo carotid intima-media thickness measurements. A is of equal or greater importance than raising of HDL-C in an effort to reduce overall risk of the individual. This also explains, Mercié P, Thiébaut R, Lavignolle V, et al Evaluation of cardio- why in some of the statin trials baseline levels of HDL were vascular risk factors in HIV-1 infected patients using ca- strongly associated with the extent of benefit from LDL-C lo- rotid intima-media thickness measurement. Ann Med Outcomes of several prospective intervention studies with Mercié P, Thiébaut R, Aurillac-Lavignolle V, et al Carotid inti- statins and fibrates have been interpreted as proofs for the be- ma-media thickness increases over time in HIV-1 infected neficial effect of increasing HDL-C on CHD prevention. Howe- ver, it is important to emphasize that these studies used fibrates Salonen J, Salonen R Ultrasound B mode imaging in observa- tional studies of atherosclerosis. Circulation 1993; and statins which exert a broad spectrum of metabolic effects, only one of which is the moderate increase in HDL-C. These Thiébaut R, Aurillac-Lavignolle V, Bonnet F et al. Change in studies do only show, that patients with low HDL-C and addi- atherosclerosis progression in HIV-infected patients: tional risk factors benefit from treatment with fibrates or statins.
ANRS Aquitaine Cohort, 1999-2004. AIDS 2005; 19: 729- Currently, only half of the coronary events are prevented by the conventional interventions including lipid- and blood pres-sure lowering therapies. Therefore, effective modification ofHDL metabolism remains an attractive target for the develop-ment of new regimens of anti-atherogenic drug therapy.
Changes of HDL concentration, composition and
hough an increase in HDL-cholesterol concentration was obtai- metabolism in HIV-infected patients
ned, it does not necessarily mean a better prognosis in the pre- vention of cardiovascular disease. Similarly, in 20 HIV-infectedpatients treated with NNRTI, a significant increase of HDL2 Servei de Medicina Interna, Hospital Universitari de Sant Joan, using NMR spectroscopy was observed.
Reus, Spain; PON-1 has been associated with the occurrence of coronary The metabolism of lipids is mediated by particles formed by heart disease, probably by inhibiting the LDL oxidation and cholesterol, triglycerides, phospholipids and apolipoproteins.
MCP-1 (a beta chemokine highly related with the atherosclerotic High Density Lipoprotein (HDL) is related to the reverse chole- plaque) secretion by the endothelial cells. Interestingly, HIV-in- sterol transport, but further pleiotropic effects have been ascri- fected patients presented with lower PON-1 serum activity than bed. Among these, it is noteworthy to describe the strong inver- healthy controls, that in turn may confer a higher cardiovascular se correlation between the HDL concentration and the occur- rence of coronary heart disease, representing an excellent candi- There are some data suggesting the influence of HDL and date to be studied in HIV-infected patients, since some of these Apo A-I on the HIV replication and on the course of AIDS di- patients present with metabolic disturbances prone to develop sease. We observed in treated patients, that the higher HDL- atherosclerosis. The so-called HDL concentration refers to the cholesterol the longer the time with undetectable HIV viral load. cholesterol content in plasma HDL, but HDL particles are not In conclusion, HIV-infection and the usual HAART-schemes homogeneous. In fact, HDL could be classified according to influence the modification not only of the cholesterol concen- size, density, electrophoretic movement and composition indica- tration, but also the distribution of several lipoproteins. This ting different features of each HDL subfraction.
phenomenon may be related to different degrees of risk to suf- The major protein compound of HDL is the apolipoprotein fer from cardiovascular disease, and so a thorough approximati- Apo A-I, but several other functional molecules have also been on to this metabolic derangements should be implemented. Si- identified, such as Apo A-II, Apo A-IV, Apo Cs, Apo E, parao- milarly, more studies should be designed to reach a better un- xonase 1 (PON-1), SAA and PAF-AH, that may be related to derstanding of the mechanisms that link HDL and Apo A-I the beneficial pleiotropic effects ascribed to HDL.
with HIV replication and the course of the acquired human im- The cornerstone of the HDL metabolism is the liver. The li- ver secretes Apo A-I and phospholipids to become discoidalHDL. This particle is involved in the recruitment and efflux ofcholesterol and phospholipids from cell membranes of peri-pheral tissues and this process is mediated by the membrane Lipoprotein pattern in HIV infected
transporter ABCA1. Free cholesterol is then esterified by LCAT patients before starting antiretroviral therapy with
and the HDL particle appears spherical (HDL3) and becomes lopinavir/ritonavir (LPV/rtv)
larger (HDL2) as it accepts more free cholesterol. The HDL2-cholesterol is transferred to Apo B containing lipoproteins or Lorenzo Magenta1, W. O. Richter2, M. Opravil3, M. Flepp4, being cleared by the SR-B1 receptor mainly located in the liver.
O. Keiser5, H. Bucher6, H. Drechsler7, P. Schmid8, J.M. Evison9, It is especially relevant to consider this phenomena in HIV- infected patients because they are under the influence of a chro- 1Servizio di malattie infettive, Ospedale Regionale di Lugano, nic infection plus, most of them, under highly active antiretrovi- Switzerland; 2Institute for Lipoprotein Metabolism, ral therapy (HAART), and both conditions are known to influ- Windach/Munich, Germany; 3Abteilung Infektionskrankheiten, ence the plasma concentration of lipids and lipoproteins. HIV- Universitätsspital Zürich, Switzerland; 4Zentrum für infected patients naïve for HAART presented with low HDL- Infektionskrankheiten, Klinik im Park, Zürich, Switzerland; cholesterol and Apo A-I plasma concentrations. Although data SHCS Coordination and Data Center, Lausanne, Switzerland 6 Basel Institute for Clinical Epidemiology, Switzerland 7Klinik in this issue is scarce, HDL-cholesterol concentration show a fur Infektiologie, Universitätsspital Basel, Switzerland; trend to decrease as the infection progresses. Further, HDL- 8Fachbereich Infektiologie, Kantonsspital St Gallen, Switzerland; cholesterol is positively correlated with the course of CD4 cell 9Klinik and Poliklinik für Infektiologie, Inselspital Bern, counts and conversely, an inverse correlation between Apo A-I and HIV-viral load has been observed.
The HIV-infection and the generalization of HAART have introduced metabolic disturbances, such as lipodystrophy and low HDL-cholesterol concentrations. The use of non-nucleosi- Protease inhibitor (PI) associated dyslipidemia has raised con- de reverse transcriptase inhibitors (NNRTI) and recent protea- cerns about increased cardiovascular risk in HIV infected pati- se Inhibitors (PI) have been associated with an interesting in- crease in the HDL-cholesterol concentration. However, ourdata supports that these changes may be under the influence of the genetic background, and several polymorphisms have been To get information on changes of lipoprotein pattern (including reported to influence the course of the lipid profile, such as apolipoproteins) in HIV-infected patients on a LPV/rtv-contai- MDR-1 C3435T, Apo C-III–455C/T and –482C/T.
ning regime. Now baseline data is available for 65 patients of the The composition, size or distribution of HDL in HIV-infec- Swiss HIV Cohort, previously naive for PI and NNRTI. Only ted patients remain poorly studied. In 49 HIV-infected patients, twelve percent of patients were NRTI experienced (mean expo- the electrophoretic pattern was similar to that observed in pati- ents with coronary heart disease, consisting with low levels ofcholesterol-rich-alpha-1 HDL. After the implementation of a PI regimen, the subfraction pre-beta-1 and pre-alpha-1 of HDL Fasting lipid parameters (total cholesterol (TC); triglycerides showed a significant increase. These results showed that alt- (TG); HDL-C; LDL-C; VLDL-C; VLDL-TG; VLDL Apo B- 100; LDL Apo B-100; Apo A-I; Apo B; Apo B-48; Apo C-II; Remnant lipoproteins and atherosclerosis
Apo C-III; Lipoprotein (a); small, dense LDL; HDL-prec.; HDL3-C; HDL2-C), glucose and uric acid were determined.
CD4+ count, HIV-1-RNA, BMI, presence of lipodystrophy, Department of Internal Medicine, Bd277, Erasmus Medical Center, Rotterdam, The Netherlands; and LPV plasma concentration were also assessed.
Patients at increased risk of coronary artery disease frequently exhibit an atherogenic lipoprotein phenotype characterized by The patients of the cohort had a median age of 41 (range 26 - elevated plasma levels of both triglyceride-rich lipoproteins 70) years, were predominantly males (83 %) and had a median (TRL) and small, dense LDL and low concentrations of HDL- BMI of 22.3 kg/m2 (range 14.4 - 29.7). Median CD4+ count cholesterol. The atherogenic lipoprotein profile is strongly lin- was 173 cells/mm3 (range 2 - 927), while 74 % had a nadir value ked to obesity, metabolic syndrome, insulin resistance, familial of < 200 cells/mm3. Median HIV-1-RNA was 5.20 log10 co- combined hyperlipidemia, and abnormalities in postprandial li- pies/ml (range 2.19 - 7.83). Lipid parameters (mg/dl) at baseline Epidemiological data have revealed that plasma TG concen- tration is an important independent risk factor. A more accurate estimation of the presence of circulating remnant particles was obtained by the analyses of plasma remnant-like particle chole- sterol (RLP-C). There is now considerable evidence to indicate that elevated levels of plasma TRL remnants are associated with increased risk of premature CAD. This association may reflect a direct effect of remnant lipoproteins on arterial lipid accumulati- on and lesion formation or alternatively may represent a charac- teristic feature of the atherogenic lipoprotein profile. Evidence has been obtained from a number of clinical studies emphasi- zing the clinical relevance of remnant analysis.
Lipoprotein (a) – Median (interquartile range) 4.6 (0.1 – 21.00) VLDL concentration, composition and metabolism
of triglyceride-rich lipoproteins (remnants) in HIV-
infected patients
In the lipoprotein fraction with a density < 1.006 g/ml no Center for HIV and Hepatogastroenterology, Grafenberger Allee ApoB48 was detected. Small, dense LDL (apolipoprotein B-100 128a, 40237 Duesseldorf, Germany; in the lipoprotein fraction with a density > 1.44 g/ml) were be-low detection limit (except two patients). Mean glucose and uric HIV-infection itself has a well known effect on serum lipids.
acid were 70.97 and 3.69 mg/dl, respectively. With the progression of the immunodeficiency LDL- and HDL-cholesterol levels decrease and triglyceride levels increase. This may be at least partially the effect of increased endogenous in- In this untreated cohort very low concentrations of total chole- terferon levels. The initiation of effective antiretroviral therapy sterol, LDL-cholesterol, HDL-cholesterol, HDL3-cholesterol, reverses to a certain extent the HIV induced dyslipidemia by in- and HDL2-cholesterol were found (as reported in literature). Li- creasing LDL-cholesterol and to a lesser extent HDL-choleste- poprotein (a) was substantially lower (median by 65 %) than in rol. However specific effects on lipids can be identified for treated HIV-positive patients or in a normal population. 29 % some antiretrovirals. An increase in triglycerides and VLDL- of patients had hypertriglyceridemia, no association with small, cholesterol is consistently reported for efavirenz and in particu- dense LDL was found. Yet, analysis of composition of VLDL lar ritonavir. Ritonavir full dose is rarely used as part of an anti- showed prevalence of triglyceride-poor particles (high cardio- retroviral therapy anymore, but as pharmacokinetic booster rito- vascular risk) at triglyceride concentrations between 150 and 220 navir is involved in daily doses ranging from 100 – 400 mg in mg/dl while at higher triglycerides particles were triglyceride- virtually all HIV-protease inhibitor regimen except nelfinavir. It rich. Apo C-II is a stimulator of lipoprotein lipase, while Apo C- has been shown previously for saquinavir and as more recent III is an inhibitor. Concentration of both Apo C’s was low, but examples for atazanavir and fos-amprenavir that the co-admini- the ratio of Apo C-III/Apo C-II was significantly associated stration with ritonavir increases triglyceride and VLDL-choleste- with triglyceride concentration. It has to be established in the rol levels compared to the unboosted use of these agents. Ho- follow-up how a virologically successful cART including wever the antiviral efficacy of the boosted administration was LPV/rtv will influence the profile of lipids, lipoproteins, and shown to be superior in all cases and therefore approved as apolipoproteins found in untreated HIV infected patients. standard therapy. Lopinavir and tipranavir can only be admini-stered in co-administration with ritonavir and may lead to a pro-found increase in triglycerides in a minority of treated patients. So far only a few anecdotal reports suggest an association bet- ween marked hypertriglyceridemia and pancreatitis or cerebralischemia qualifying this as rare events given the frequent use ofboosted protease inhibitors. A more long term adverse effectmay be an increase in cardiovascular events. In general hyper- triglyceridemia without additional risk factors, e. g. features of Longitudinal studies, which include patients enrolled in the the metabolic syndrome, is considered to have a low cardiovas- SHCS, are underway in our laboratory to evaluate the contribu- cular risk. Recent studies have shown that in hypertriglyceride- tion of 1) variant alleles of additional genes involved in lipid me- mia induced by HIV-protease inhibitors VLDL particles have a tabolism to HAART-related dyslipidemia, and 2) sequence alte- large size. This phenomenon is found in familial hypertriglyceri- rations of mtDNA to lipoatrophy. If pharmacogenetic associati- demia which is associated with a low cardiovascular risk. Howe- ons are identified and confirmed in different cohorts of patients, ver in HIV-associated dyslipidemia a proportion of patients may it may soon be reasonable to evaluate the usefulness of genetic mimic metabolic syndrome with central adiposity, insulin resi- analysis to predict which patients will develop lipid disorders stance and low HDL-cholesterol whereas other patients present with hypertriglyceridemia only. In addition the pharmacologiceffects of the antiretrovirals do interact with pre-existing condi- tions such as genetic or dietary induced lipid disorders. In the Fauvel J, Bonnet E, Ruidavets JB, et al An interaction between DAD-study an early increase in myocardial infarction was repor- apo C-III variants and protease inhibitors contributes to ted for patients on antiretroviral therapy. One of the multiple high triglyceride/low HDL levels in treated HIV patients.
baseline risk factors identified was hypertriglyceridemia. The Maher B, Alfirevic A, Vilar FJ, et al TNF-alpha promoter regi- atherogenic effect of hypertriglyceridemia is thought to be me- on gene polymorphism in HIV-positive patients with lipo- diated by VLDL-cholesterol. However no detailed data on the VLDL-particles are available in this study. In addition because Martin AM, Hammond E, Noland D, et al Accumulation of of the limited sample size of cases with myocardial infarction no mitochondrial DNA mutations in human immunodeficien- definite conclusion can be drawn, if hypertriglyceridemia was cy virus-infected patients treated with nucleoside-analogue mainly a treatment effect with antiretrovirals or independent reverse-transcriptase inhibitors. Am J Hum Genet 2003; McComsey G, Bai RK, Maa JF, et al Extensive investigations of mitochondrial DNA genome in treated HIV-infectedsubjects: beyond mitochondrial DNA depletion. J AIDS Genetic Factors and susceptibility to antiretroviral
therapy-associated lipid disorders
Nolan D, Moore C, Castley A, et al Tumour necrosis factor- alpha gene-238G/A promoter polymorphism associatedwith a more rapid onset of lipodystrophy. AIDS 2003; 17: Infectious Diseases Service, University Hospital Lausanne, Tarr PE, Taffe P, Bleiber G, et al Modeling the influence of ApoC3, ApoE, and TNF polymorphisms on the risk of Dyslipidemia and lipodystrophy occur in some but not all HIV- antiretroviral therapy-associated lipid disorders. J Infect infected patients, despite similar exposure to highly active anti- retroviral therapy (HAART) and comparable demographic, im-munologic, and virologic characteristics. This discrepancy mightbe related to host genetic factors.
Fauvel (AIDS 2001) showed an association of hypertriglyceri- What is proved for lipoprotein (a) as cardiovascular
demia with variant alleles of APO C-III (the single nucleotide risk factor?
polymorphisms -482 C>T, -455 C>T, and +3238 C>G) in 60PI-treated men. Maher (AIDS 2002) and Nolan (AIDS 2003) identified associations of TNF-238 G>A with lipoatrophy, whi- Medizinische Klinik des Diakoniekrankenhauses, Speyrer Strasse le studies of the contribution of mitochondrial DNA mutations 91-93, 68163 Mannheim, Germany, did not show clear-cut results (Martin Am J Hum Genet 2003,McComsey J AIDS 2005).
Lipoprotein (a) is composed of low density lipoprotein (LDL) We have recently reported on the association of APO E and particles additionally containing apolipoprotein (a), a glycopro- APO C-III variants with hyperlipidemia in a longitudinal study tein, covalently linked to apolipoprotein B. Plasma concentrati- of 329 HIV-infected patients enrolled in the Genetics Project of ons of lipoprotein (a) vary over a 1000-fold-range, and the dis- the Swiss HIV Cohort Study (SHCS) (Tarr J Infect Dis 2005).
tribution of levels is highly skewed, with most whites and Asians Carriers of variants of both APO C-III and APO E were at risk having low levels. The distribution of plasma levels in blacks is for extreme and sustained hypertriglyceridemia when exposed to less skewed, and the median level is 2 to 4 times greater than in RTV. The contribution of the APO E ε4 allele was quantitative- ly similar to the non-HDL-cholesterol-increasing effect of PI A meta-analysis of 27 prospective studies, which included treatment. No association between TNF-238 G>A and lipoatro- 5436 coronary heart disease cases, demonstrated a consistent, phy was observed. Our study highlights the issues of appropria- positive association between high plasma levels of lipoprotein te methodology and statistical power in genetic association stu- (a) and coronary atherosclerosis in whites. Comparison of indi- dies. The influence of the genetic variants on lipids was analysed viduals in the top third of lipoprotein (a) measurements with over >3 years of follow-up, during which patients served as those in the bottom third in each study yielded a combined risk their own controls, through multiple changes of HAART. Lon- ratio of 1.6 (95 % confidence interval 1.4 1.8). It was concluded gitudinal modeling of lipid levels in large numbers of patients that this clear association between lipoprotein (a) and coronary may represent the most powerful approach to quantitating the heart disease needs further studies to determine the extent to contributions of genotype and HAART to HIV-related lipid dis- orders. In contrast, cross-sectional analyses of lipid levels at a A very recent study emphasizes that high lipoprotein (a) pre- single time point during HAART exposure seem to be underpo- dicts risk of angina, and that the risk is substantially increased wered to detect the genetic effects.
with high concomitant LDL-cholesterol. In this case control study 195 men who subsequently developed angina were com- HIV-infected patients who required no antiretroviral therapy pared to 195 men who remained free of cardiovascular disease (n = 55, Stuttgart cohort) were compared to treated patients (n for 5 years. In this study, a lipoprotein (a) concentration measu- = 245). Patients from a different cohort (Swiss Cohort, n = 65) red by ELISA above the 95th percentile (~ 70 mg/dl) was asso- who required antiretroviral treatment had a much lower median ciated with an almost fourfold risk. Using a commercially availa- lipoprotein (a) concentration. 14 out of 65 (22 %) patients had ble test a strong, a nearly 12-fold increase in relative risk for an- lipoprotein (a) above 30 mg/dl (three above 70 mg/dl (5 %)), gina was found at lipoprotein (a) concentrations above 30 mg/dl LDL-cholesterol was < 100 mg/dl in all patients. 75 HIV-infec- with concomitantly elevated LDL-cholesterol above 160 mg/dl.
ted patients in the Stuttgart and Duesseldorf cohorts were follo- Other studies have reported comparable findings, the increase wed longitudinally up to two years. After initiating HAART only in risk was ~ fourfold in patients with elevated lipoprotein (a) about half of the patients showed an increase of lipoprotein (a).
and concomitantly elevated LDL-cholesterol. No association was found with any type of drug therapy, neither As no lifestyle or drug therapy of elevated lipoprotein (a) NRTI nor NNRTI or protease inhibitors. From this data hypo- exists, data of intervention studies are lacking. Only in one very thesis I can only partly be accepted: A significant number (about small trial lipoprotein (a) was lowered by extracorporeal elimina- one fifth) of HIV-infected patients do have an increased risk for tion without showing an additional positive effect on coronary coronary heart disease, but this seems to be independent of anti- heart disease. Yet, as no levels below 30 mg/dl could be obtai- ned, the results of this study warrant further investigation. Apolipoprotein (a) contains multiple repeated kringle do- II. We then compared the above data from HIV positive pati- mains that are similar to a sequence found in plasminogen. Dif- ents with data from HIV negative patients (Nuremberg Cohort, fering numbers of kringle sequences in apolipoprotein (a) give patients from a cardiology center) with or without coronary rise to lipoprotein (a) isoform size heterogeneity. In addition to heart disease. Median lipoprotein (a) was 17 mg/dl in patients elevated lipoprotein (a) plasma concentration apolipoprotein (a) without coronary heart disease (interquartile range 8.0 – 46.5 isoform size has been discussed as a risk factor for coronary mg/dl, n = 200). 44 patients (22 %) had a lipoprotein (a) above heart disease, but this could not be shown in all studies. 70 mg/dl or above 30 mg/dl plus LDL-cholesterol > 160 A problem which has to be solved in the future is the enor- mg/dl. Median lipoprotein (a) was 22.5 mg/dl in patients with mous interassay variance of lipoprotein (a) determination espe- coronary heart disease (interquartile range 9.0 – 61.5 mg/dl, n = cially at high concentrations. Until this problem has been sol- 154), 39 patients (25 %) had lipoprotein (a) above 70 mg/dl or ved, follow-up data have to be obtained by the same assay with above 30 mg/dl plus LDL-cholesterol > 160 mg/dl. 80 % of the patients with lipoprotein (a) above 30 mg/dl were treated withlipid-lowering drugs. While median lipoprotein (a) levels maynot indicate risk for coronary heart disease it is helpful to focus Lipoprotein (a) concentration in HIV-infected
on very high lipoprotein (a) levels: 22 % with coronary heart di- patients
sease had lipoprotein (a) > 70 mg/dl compared to 5 % withoutcoronary heart disease.
Tim Niehues, Jennifer Neubert, Nadine Thiemeyer In summary, a substantial part of HIV-infected patients is at Zentrum für Kinderheilkunde der Heinrich-Heine-Universität, increased risk for coronary heart disease due to elevated lipo- Moorenstraße 5, 40225 Düsseldorf, Germany; protein (a). Concentrations are not higher than in a normal po- pulation and appear to be lower as compared to a non-HIV-in-fected cohort with coronary heart disease. The value of lipopro- Lipoprotein (a) is thought to be involved in the pathogenesis of tein (a) as a risk factor for cardiovascular disease in HIV-infec- atherosclerosis. An elevated lipoprotein (a) above 70 mg/dl or ted patients needs to be evaluated in prospective cohort trials. elevated lipoprotein (a) above 30 mg/dl with concomitantly ele-vated LDL-cholesterol > 160 mg/dl seem to be risk factors forcardiovascular disease. We discuss the following hypotheses: I.
Importance of non-lipid risk factors for coronary
In a significant subset of HIV infected adults and children lipo- heart disease in HIV-infected patients
protein (a) is elevated and this correlates with antiretroviraltherapy. II. In HIV negative individuals with coronary heart di- sease lipoprotein (a) is elevated to a similar degree as in HIV po- Department of Cardiology, University of Duisburg-Essen, sitive individuals. Published as well as new data from HIV infec- Medical School, Hufelandstr. 55, D-45122 Essen, Germany; ted adults and children are reviewed.
I. In a group of 300 HIV-positive adults followed at a HIV clinic I. Differences due to acquisition of HIV-infection in Stuttgart (Germany) (266 men, 34 women, mean age 40.4 ± Cardiovascular risk factors of 309 HIV-infected adults (HIV-ac- 9.2 years, 245 treated with antiretroviral drugs) median lipopro- quisition: 59.2 % by homosexual contact (group 1), 28.5 % by tein (a) was 13 mg/dl (interquartile range 4 – 48 mg/dl). 59 pati- heterosexual contact (group 2), 9.1 % by intravenous drug abuse ents (19,6%) had either lipoprotein (a) > 70 mg/dl or >30 mg/dl (group 3) and 3.2 % by blood transfusion (group 4)) were analy- plus an elevated LDL-cholesterol > 160 mg/dl. 104 patients sed. Overall 10-years probability for cardiovascular events was (34.6 %) had a lipoprotein (a) > 30 mg/dl. Similarly, the preva- analysed by the Framingham algorithm.
lence of lipoprotein (a) > 30 mg/dl in other smaller cohorts was22 – 33 %. In 53 children on an antiretroviral therapy median li- Results: Tobacco use was more common in group 1 subjects poprotein (a) was 21 mg/dl (interquartile range 8.0 –, compared with group 2 subjects (67 % vs. 52 %; p < 0.05). Ad- 12 of them (22 %) had a lipoprotein > 70 mg/dl and two (4 %) ditionally, group 1 subjects exhibited elevated total cholesterol above 30 mg/dl plus LDL-cholesterol above 160 mg/dl and 8 (5.6 ± 0.1 mmol/l vs. 4.8 ± 0.3), LDL-cholesterol (3.6 ± 0.1 (15 %) above 30 mg/dl plus LDL-cholesterol > 110 mg/dl. mmol/l vs. 2.8 ± 0.2) and triglyceride concentrations (3.2 ± 0.3 mmol/l vs. 1.7 ± 0.2) compared with group 3 (all p < 0.05). No tient population. In the future, further increase of cardiovascular significant differences between the groups were detected in glu- events in HIV-infected patients may be expected.
cose metabolism. The overall 10-years probability for cardiovas-cular events was significantly higher in group 1 compared withgroup 2 and group 3 (12.2 ± 0.8 % vs. 6.6 ± 0.9 % and 7.9 ± 1.6 Impact of lipodystrophy on lipids in HIV-infected
Conclusions: The cardiovascular risk profile differs between sub-groups of HIV-infected individuals, leading to significant higher probability of cardiovascular events in group 1 subjects. The risk Clinical Institute of Infections and Immunology, Institu of premature atherosclerosis by HIV-infected individuals and d'Investigacions Biomediques August Pi i Sunyer, Hospital therapeutic options remains to be established.
Clinic, Barcelona, Spain; Lipodystrophy in HIV-1-infected patients represents an adverse Cardiovascular risk factors of 309 HIV-infected adults, inclu- effect of antiretroviral therapy, not limited to a specific drug or ding 240 males were analysed. Overall 10-years probability for class of drugs. It is not completely known whether lipodystro- cardiovascular events was evaluated by the Framingham algo- phy is one unique syndrome or several different overlapping syndromes. Metabolic features such as increased levels of trigly- Results: Gender differences were detected in cardiovascular risk cerides, total, LDL- and VLDL-cholesterol, reduced HDL-cho- factors such as lipid values, blood pressure and the rate of smo- lesterol, insulin resistance, and body fat abnormalities consisting king. Tobacco use was much more common in HIV-infected of a lipoatrophy-generalized decrease of subcutaneous fat with males compared with HIV-infected females (67.5 % vs. 49.3 %; or without lipohypertrophy, intra-abdominal, breast or dorso- p < 0.001). Although no significant difference was noticed in to- cervical accumulation have been commonly reported, although tal cholesterol (5.49 ± 0.09 vs. 5.53 ± 0.19 mmol/l, p = 0.84), the intensity and the associations of those changes among them- the HDL-cholesterol concentration was significantly lower (1.09 ± 0.03 vs. 1.36 ± 0.06 mmol/l, p < 0.001) and the triglyceride Metabolic alterations observed in HIV-infected patients concentration higher (3.01 ± 0.21 vs. 2.06 ± 0.26 mmol/l, p = might be either a consequence of HAART, HIV infection, or 0.02) in HIV-infected males compared to HIV-infected females.
body fat changes, or the combination of all three. Potential Additionally, systolic blood pressure was higher in HIV-infected exclusive impact of body fat abnormalities on lipids in HIV-in- males compared with HIV-infected females (123.1 ± 1.1 vs.
fected patients is therefore hard to be elucidated.
115.4 ± 2.1 mmHg, p < 0.01). No significant differences were Only recent studies have indicated that adipose tissue is not a detected in HbA1c concentrations between both groups (5.15 ± passive site of energy storage but is also an endocrine organ 0.07 % vs. 5.31 ± 0.11, p = 0.26). The overall 10-years probabi- with broad secretory activity of adipocytokines such as TNF-α, lity for cardiovascular events was 8.7 % (median) in HIV-infec- IL-6, IL-8, adiponectin, leptin and resistin. Adipocytokines are ted males and 1.7 % in HIV-infected females (p < 0.0001). bioactive peptides that may play an important role in the regula- Conclusions: In the present study, we observed gender differen- ces in the cardiovascular risk profile of HIV-infected individu- Dysfunction of fat cell differentiation and increased apoptosis als. The risk of premature atherosclerosis and associated cardio- observed in HIV-infected patients with lipodystrophy may lead vascular events was significantly higher in HIV-infected males.
to defective endocrine function of adipose tissue. Increased ex-pression of TNF-α, IL-6 and IL-8, and decreased levels of adi- ponectin and leptin have so far been described.
309 HIV-infected adults were analysed. Patients were divided While leptin levels are related to subcutaneous fat content and into four groups: 18 - 30 years (group 1), 31 - 40 years (group 2), the level of adiposity, and adiponectin levels are associated with 41 - 50 years (group 3), > 50 years (group 4). Overall 10-years measures of fat distribution, both leptin and adiponectin may probability for cardiovascular events was evaluated by the Fra- play an important role in metabolic abnormalities and both are altered in HIV lipodystrophy syndrome.
Results: Differences between the groups were detected in car- Plasma adiponectin and leptin concentrations were inversely diovascular risk factors including changes in lipid- and glucose and directly associated with plasma Apo B-48, Apo C-III, HDL- metabolism. Lipid values increased with elevated age, such as to- cholesterol, triglycerides, VLDL-Apo B, and VLDL-triglyceri- tal cholesterol concentration (Mean ± SEM in group 1 vs. group des. These data suggest that plasma adiponectin concentration 4: 4.71 ± 0.20 to 6.36 ± 0.21 mmol/l, p < 0.05), LDL-choleste- may not only link abdominal fat, insulin resistance, and dyslipi- rol concentration (2.86 ± 0.17 vs. 4.17 ± 0.21 mmol/l, p < 0.05) demia, but may also exert an independent role in regulating con- and triglyceride concentration (1.56 ± 0.14 vs. 3.48 ± 0.40 centration of free fatty acids and triglycerides metabolism. Since mmol/l, p < 0.05). HDL-cholesterol concentration did not it is stimulated by insulin and inhibited by TNF-alpha, insulin show a significant difference (1.15 ± 0.03 mmol/l). Glucose resistance and TNF-alpha expression may contribute to this ef- concentration increased with elevated age in HIV-infected pati- ents (5.28 ± 0.19 vs. 6.46 ± 0.24 mmol/l, p < 0.05), but there HIV-lipodystrophy syndrome is associated with an accelera- was no significant difference in HbA1c - concentration, blood ted rate of lipolysis, increased release of free fatty acids that re- pressure and smoking rate between the groups. The overall 10- sults in increased hepatic fatty acid re-esterification to triglyceri- years probability for cardiovascular events was higher in group 1 des, and impaired triglyceride storage could lead to hypertrigly- (median: 1.9 %) than in group 4 (20.5 %; p < 0.01). ceridemia and decrease of HDL-cholesterol. Some clinical trials, Conclusions: The risk of cardiovascular events is related to the however, failed to show this dependence.
age in HIV-infected patients. Therefore, an increased duration Other derangements have been described, although their rela- of life due to a more effective antiretroviral therapy will have a tionship with the lipodystrophy syndrome and its impact on me- significant impact on the rate of cardiovascular events in this pa- tabolic alteration has not been clearly established. Knowledge of some aspects of this problem has increased in recent years, but Metabolic abnormalities and lipodystrophy
many important questions remain to be solved in this cascade of syndrome in HIV-infected children in Poland
Jolanta Popielska, Magdalena Marczyska, Sabina Dobosz, Department of Children’s Infectious Diseases Medical Academy, Accumulation of dorsocervical fat (“buffalo hump”)
in HIV-infected patients.
A case control study (LIPOCER STUDY)
Metabolic abnormalities and clinical signs of lipodystrophy areknown adverse effects of antiretroviral therapy in HIV infected Rosario Palacios1, M. J. Galindo2, J. A. Arranz3, F. Lozano4, children. The consequence may be early atherosclerosis e. g.
V. Estrada5, A. Rivero6, D. Morales7, V. Asensi8, A. del Arco9, A. Muñoz10, Jesús Santos1, for the Grupo de Estudio de Alteraciones Estimation of prevalence of metabolic abnormalities and lipody- 1Hosp. Virgen de la Victoria, Infectious Diseases Unit, Málaga, strophy in HIV infected children receiving Highly Active Anti- Spain, 2Hosp. General, Valencia, Spain, 3Hosp. Principe de Asturias, Alcalá de Henares, Spain, 4Hosp. de Valme, Sevilla, Spain, 5Hosp. Clínico San Carlos, Madrid, Spain, 6Hosp. Reina 57 children (aged 10 months - 17 years) were included into the Sofía, Córdoba, Spain, 7Hosp. Virgen Macarena, Sevilla, Spain, study. The patients history was documented and physical exami- 8Hosp. General de Asturias, Oviedo, Spain, 9Hosp. Costa del nation was done every 12 weeks. Laboratory tests included: Sol, Marbella, Spain, 10Hosp. Infanta Cristina, Badajoz, Spain; triglycerides, total cholesterol, LDL-cholesterol, HDL-choleste- rol, and glucose. In 41/48 patients body composition was mea- sured twice by Bioelectrical Impedance Analysis (BIA). Patients Lipodystrophy is very common in HIV-patients on HAART.
were divided into 2 groups: 1) below 3 years of age (mean 24 However, buffalo hump (BH) is only reported in 2 - 13% of months) – 9 children; 2) above 3 years (mean 8 years and 9 HIV-infected patients. Our aim was to analyse the prevalence of months) – 48 children. 3 years of age was estimated to be the BH in HIV-infected patients on HAART and the factors asso- border for the development of lipodystrophic signs. Metabolic abnormalities were observed in 54/57 children: in all Multicenter, observational, 1:1 case-control study of HIV outpa- children < 3 years and in 45/48 of older children. There were tients from 10 Spanish institutions. Cases: HIV patients with increased levels of triglycerides in 50 cases, of cholesterol in 45 dorsocervical fat accumulation. Controls: HIV patients from the cases and low HDL-cholesterol in 14 cases. same cohort, controlled by age (± 5 years), sex, and BMI (± 2,5 Lipodystrophy was found in 15/48 children > 3 years (60% kg/m2 ). Epidemiological, clinical, and analytical data were girls and 40% boys). All received HAART (mean time: 4 years collected. Statistic program: SPSS® 10.0. and 8 months), their mean age was 9 years and 3 months; 5/15 had AIDS; 5/15 had severe immunodeficiency. The characteri- A BH was reported in 80 (1.8%) patients from a cohort of 4,214 stics of the group without lipodystrophy (33/48) were: 60.6% patients on HAART followed up in the participant institutions.
boys, 39.4% girls, mean age 8 years and seven months; 9/33 had Four of the patients with a BH were excluded as no matched AIDS; 14/33 severe immunodeficiency. Family history was bur- controls could be found. Those patients with a BH had a longer dening in 60% cases in both groups. Metabolic abnormalities evolution of HIV infection (139 vs. 107 months; p = 0.0001), were observed in all children with lipodystrophy and 90,9% more exposure to PI (91 vs. 68 %; p = 0.002), EFV (60 vs. 40 without lipodystrophy. All children with lipodystrophy were %; p = 0.032), and d4T (91 vs. 54 %; p = 0.0001), higher waist- treated with stavudine, often stavudine and didanosine. Of the to-hip ratio (0.98 vs. 0.93; p = 0.0001), triglyceride levels (230 children with lipodystrophy 6 had lipoatrophy (5 boys, 1 girl), vs. 156 mg/dl; p = 0.0001), and CD4 cell count (622 vs. 513/µl; one girl had lipohypertrophy, 9 mixed forms (8 girls, 1 boy); of p = 0.021), and lower HDL-cholesterol levels (43 vs. 52 mg/dl; 13/15 children examined with BIA 23% had normal, 23% p = 0.001); they were more likely to have lipoatrophy (83 vs. 33 decreased and 54% increased fat mass in comparison with %; p = 0.0001), gynaecomasty (16 vs. 1 %; p = 0.005), neuropa- 28/33 girls without lipodystrophy (29%, 7%, and 64%).
thy (8 vs. 0%; p = 0.028), and prior metabolic disorders (53 vs.
18 %; p = 0.0001). In the multivariate analyses, only increasing Metabolic abnormalities in HAART treated children are fre- time of exposure to d4T (for each 6 months increase: 5.82, 95 % quent (95%). Advance of disease and time of HAART treatment CI 5.70 - 5.94; p = 0.0073), and lipoatrophy (8.04, 95 % CI 2.93 (especially with stavudine and didanosine) increase risk for this - 22.02; p = 0.00001) were independently associated with a BH.
Conclusions: Although lipodystrophy is very frequent amongHIV-infected patients on HAART, BH is an uncommon kind offat redistribution in this population. It was related to time of ex-posure to d4T and lipoatrophy.
Extended follow-up of cardiovascular and cerebro-
Hospitalizations for Coronary Heart Disease and
vascular outcomes and deaths in a retrospective co-
Myocardial Infarction Among Northern California
hort of HIV patients treated in US Veterans Affairs
Men With and Without HIV-1 Infection
Daniel B. Klein, Leo B. Hurley, Charles P. Quesenberry, and Stephen Veterans Affairs Quality Enhancement Research Initiative for Kaiser Permanente Medical Center, Hayward, California, USA; HIV and the Center for Research in Patient Oriented Care at the Veterans Affairs San Diego Health Care System, San Diego, Calif In our US population of HMO-enrolled HIV-1 infected patients Metabolic abnormalities associated with human immunodefi- we have reported increased risk of CHD and MI compared to ciency virus (HIV) infection, including dysglycemia and hyperli- the base population of HIV-1 uninfected members. We have pidemia, are increasingly prevalent, and there is growing concern also examined the differential risk of these events in patients ex- about associations between treatment, lipids and the risk of ac- posed vs. unexposed to the protease inhibitor (PI) class of anti- celerated cardiovascular and cerebrovascular disease. Our group retroviral agents. We have found increased risk with exposure previously published an outcomes study that reported on car- that appears to increase with duration of exposure, however diovascular/cerebrovascular outcomes among HIV treated indi- with less certainty than other researchers. The documented viduals in the Veterans Administration system (Bozzette et al.
atherogenic lipid changes consequent to PI therapy for HIV-1 N Engl J Med. 2003 Feb 20; 348(8): 702-10). We used admini- infection contribute to CHD/MI risk. Our current work upda- strative data to study of the risk of cardiovascular and cerebro- tes previous risk estimates as exposure time and events accumu- vascular disease and death among the 36,766 patients who recei- late. We also describe how changes in medical practice might ex- ved care for HIV infection at US Veterans Affairs facilities bet- plain the relatively muted effect of PI exposure and an apparent recent reduction in CHD and MI event rates despite increased For antiretroviral therapy, 70.2 percent of the patients recei- ved nucleoside analogues, 41.6 percent received protease inhibi- tors, and 25.6 percent received nonnucleoside reverse-transcrip- We continue to monitor and compare hospitalization rates for tase inhibitors for a median of 17 months, 16 months, and 9 CHD (ICD9 410-414) and separately for MI (ICD9 410) among months, respectively. Patient-level regression analyses indicated a cohort of HIV(+) males and among a random sample of pre- that there was no relation between the use of nucleoside analo- sumed HIV(-) males. Persons studied were members of the Kai- gues, protease inhibitors, or nonnucleoside reverse-transcriptase ser Permanente Northern California health plan, a large closed inhibitors and the hazard of cardiovascular or cerebrovascular system HMO, and had no prior CHD events. Observational fol- events, but the use of antiretroviral drugs was associated with a low-up (FU) began in 1996 and now extends through 6/30/05.
decreased hazard of death from any cause. Among HIV+'s, person-years (PY) of FU was assigned as either We concluded that the use of newer therapies for HIV was no/pre-PI exposure vs. during/post PI-exposure. A person associated with a large benefit in terms of mortality that was not could contribute PY to both exposure categories. Age-adjusted substantially diminished by any increase in the rate of cardiovas- CHD and MI rates for ages 35-64 were calculated overall for cular or cerebrovascular events or related mortality. Shortly the- HIV+'s and HIV-'s, and by PI exposure and duration of PI ex- reafter, the carefully conducted DAD study used a prospective posure for HIV+'s. Traditional risk factors, antiretroviral pre- pseudo-cohort design to show similar overall benefits to treat- scriptions and lipid measurements were assessed from electronic ment but an increased risk of cardiovascular events. Both groups conclude that prolonged survival among HIV-infected patients meant that longer-term observation in the clinical set- In the 9.5-year observation period, 5430 HIV+ patients contri- ting and in the prospective cohort study were indicated.
buted 26,882 PY of FU (median 4.6) and there were 140 CHD We have since repeated and somewhat extended this analysis events (86 MIs). Over forty thousand HIV-'s contributed 307K on an updated VA cohort. The expanded cohort includes 41,213 PY of FU. Among HIV+'s exposed to PIs, median PI exposure patients and extends follow-up from 121,936 to 168,611 patient- was 4.3 years. Age-adjusted CHD and MI rates among HIV+'s years. The number of patients having at least 4 years of exposu- continue to be roughly twice that of HIV-'s (CHD: 6.0 vs. 2.9 re to any ARV increased from 4,808 in the original cohort to events/1000 PY, p < 0.0001; MI: 3.6 vs. 2.2, p = 0.002). Among 8,582 in the 1993-2003 cohort. There were 1,735 cardiovascular HIV+'s, overall rates for never vs. ever PI exposure were not admission and 17,558 deaths in the updated cohort. Rates of significantly different but were suggestive of an effect (CHD: cardiovascular admissions were steady at about 1 per 100 pati- 4.8 vs. 6.9, p = 0.09; MI: 3.0 vs. 4.2, p = 0.20). The age-adjusted ent-years while death rates continued to decline to a low of 5.2 relative risk for CHD hospitalization per two years of PI expo- per 100 patient-years in 2003. Differences between cumulative sure was 1.05 (95% CI: 0.89, 1.30, p = 0.22); relative risk for MI survival and cumulative survival with cardiovascular disease continued to be trivial. However, preliminary modeling may suggest that trends of interesting the risk of cardiovascular di- Even in the absence of PIs, HIV(+) persons have twice the rate of hospital CHD and MI as their HIV(-) counterparts. Traditio-nal risks, including the dyslipidemia associated with HIV infec-tion (low HDL), as well as chronic inflammation are a likely ba-sis for this observation. We are not seeing a worsening of theapparent initial rise in the number and rate of CHD and MIevents. This is possibly due to increased use of ‘lipid-friendly’antiretroviral regimens and greater attention to coronary risk inHIV-infected individuals. Relationship between prolonged exposure to com-
[1.11 - 1.24] increased risk of MI per additional year of cART bination antiretroviral therapy (cART) and myocar-
exposure. Similar results were found after inclusion of repeat dial infarction (MI): effect of sex, age and lipid
MIs (1.18 [1.09 - 1.28]), inclusion of only definite MI (58.5 % of changes. Results from the D:A:D Study.
MIs) (1.22 [1.11 - 1.35]), and restricting the analysis to naïve pa-tients (n = 4161) at entry (1.39 [0.93 - 2.08]). Although the absolute rate of MI was higher in men than wo- Copenhagen HIV Programme, Dept 044, Hvidovre University men (2.04 [1.30 - 3.21]), the RR associated with cART was simi- Hospital, Hvidovre, Copenhagen, Denmark; lar in men (1.14 [1.06 - 1.24]) and women (1.38 [1.07 - 1.76], p-value for interaction 0.51). The relationship was similar in youn- ger and older patients (men > 45 and women > 55 years; p-va- Combination antiretroviral therapy (cART) for the treatment of lue for interaction 0.41). Including time-updated levels of serum HIV-1 infection can induce metabolic adverse effects, including total cholesterol (RR 1.15 [1.06 - 1.25] per mmol/l), HDL-cho- dyslipidemia and insulin resistance, which confers potential risk lesterol (0.60 [0.42 - 0.88] per mmol/l), and triglycerides (1.64 for cardiovascular disease (CVD). Prior data from the D:A:D [0.98 - 2.74] per log2) in the same model, reduced the associati- Study suggest an association of cART exposure with an increa- on of additional year of cART with MI to 1.10 [1.01 - 1.19]. Ad- sed risk of MI. We investigated if the linear trend previously re- justment for lipid lowering medication did not further affect the ported continues with further cART exposure, whether it is mo- association between cART exposure and MI. dified by age or sex, and possible mechanisms for this relations- These findings suggest that while the overall absolute risk of MI remains modest in this relatively young population, the risk con- D:A:D is a prospective multi-cohort study investigating the inci- tinues to increase with longer exposure to cART over the first 7 dence of CVD and factors that affect this. 23,437 HIV-infected years of use. Dyslipidemia explained part but not all of the asso- persons (24% women) from 188 clinics in Europe, USA and ciation of cART with risk of MI. Conversely, our data do not Australia were enrolled from 1999 to 2001, and followed pros- suggest any association with level of immune deficiency, HIV- pectively thereafter. Results based on follow-up to February RNA or duration of HIV-infection [data not shown]. The relati- 2004. Incidence rates of first prospective MI (/1000 person- ve increase in risk appears similar in men and women, and in ol- years (PY)), and relative rates (RR) of factors associated with MI der and younger subjects. Based on the current evidence, clinici- from Poisson regression models are reported.
ans are encouraged to carefully monitor the risk of CVD in HIV-patients receiving cART, and to intervene according to At present the study population has contributed more than 76,500 person years of follow-up (PY). During this time, 277patients experienced a first MI. The MI incidence increasedfrom 1.39/1000 PY in those not exposed to cART, to These findings were first reported at the 12th CROI, Boston 2005 (W.
6.07/1000 PY in those exposed for >6 years (RR compared to The D:A:D Study receives funding from The Oversight no exposure: 4.38 [95% CI: 2.39 - 8.04], p = 0.0001). After ad- Committee for The Evaluation of Metabolic Complications of justment for other potential risk factors, there was a 1.17 fold



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